Triazine derivatives for treating diseases relating to neurotrophins

ABSTRACT

There is provided herein a compound of formula (I) wherein R 1 , R 2 , n, X, Q, L, m, R 3  and p are as defined herein, which compounds are useful in the treatment of treatment of diseases characterised by impaired signalling of neurotrophins and/or other trophic factors, such as Alzheimer&#39;s disease and the like.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national stage filing, under 35 U.S.C. §371(c), of International Application No. PCT/GB2019/050523, filed onFeb. 26, 2019, which claims priority to United Kingdom PatentApplication No. 1810667.4, filed on Jun. 28, 2018, and Swedish PatentApplication No. 1850217-9, filed on Feb. 26, 2018.

FIELD OF THE INVENTION

This invention relates to the pharmaceutical use of certain compounds inhuman medicine, to pharmaceutical compositions comprising suchcompounds, as well as to novel pharmaceutically-active compounds. Inparticular, the invention relates to the use of these compounds andcompositions in methods for the treatment and/or prevention of diseasescharacterised by impaired signalling of neurotrophins and/or othertrophic factors.

BACKGROUND OF THE INVENTION

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Nerve growth factor (NGF), Brain Derived Neurotrophic Factor (BDNF) andneurotrophin-3 (NT-3) and neurotrophin-4/5 all belong to theneurotrophin protein family. These hormones act through a class ofreceptor tyrosine kinases called tropomyosin-receptor kinase (Trk).Ligand binding to Trks initiates receptor dimerization andautophosphorylation of the kinase domain, which activates the kinaseactivity of the receptor. This results in further receptorphosphorylation at Tyr490, Tyr751 and Tyr785 of TrkA (or theirequivalent residues in other Trk receptors). This phosphorylation leadsto adaptor binding sites that couple the receptor to SHC adaptor protein1 (SHC-1), phosphoinositide 3-kinase (PI3K) and phospholipase Cγ1(PLCγ1). The coupling of adaptor proteins to the receptor initiatesseveral different cellular events leading to e.g. neurite outgrowth andaxonal elongation. These receptors, and their signalling pathways, playa pivotal role in many key processes in the brain e.g. hippocampalneurogenesis, synaptic plasticity, and long-term potentiation, aproposed mechanism underlying memory formation at the level of thesynapse. Both NGF/TrkA and BDNF/TrkB-stimulated signalling is alsonecessary for the survival and morphogenesis of neurons.

In addition to activation of Trk-receptors by classical ligand binding,there are ligand independent events that can regulate neurotrophinsignalling.

The balance between the activity of the receptor tyrosine kinase and theactivity of tyrosine phosphatases intricately regulates the levels ofphosphorylated receptor. Thus, protein tyrosine phosphatases such asPTP-1B or other phosphatases can increase neurotrophin signalling andregulate temporal and spatial activity of the Trk-receptor as well asreceptor tyrosine kinases.

Also, adenosine and adenosine agonists can mediate phosphorylation ofTrk-receptors, via a mechanism that requires the adenosine 2A (A2A)receptor. This phosphorylation of Trk-receptors is independent of ligandbinding suggesting that modulation of Trk-receptor signalling can beaccomplished by several different mechanisms.

Other key members of growth factor family are the fibroblast growthfactors (FGF 1-23) and insulin growth factors (IGF 1-2). FGFs, throughbinding to their receptors (FGFR1, FGFR2, FGFR3, and FGFR4), play a keyrole in proliferation and differentiation processes of a wide variety ofcells and tissues and thereby are involved in processes such asangiogenesis, wound healing, embryonic development and variousendocrine-signalling pathways. IGF on the other hand, has a similarmolecular structure to insulin, and binds to its receptor IGF-1Rmediating effects on growth in childhood and continuing to have anaboliceffects in adults. Both of these factors have also been implicated inthe pathogenesis of neurodegenerative disorders of the central nervoussystem (CNS) such as Alzheimer's disease (Li J S et al., Med Hypotheses,2013 April 80(4), 341-4 and Gasparini et al., Trends Neurosci. 2003 Aug.26(8):404-6).

Synapse loss and a decrease in the hippocampal volume are pathologicalsignatures of Alzheimer's disease in the brain and a number of studiessuggest that synapse loss is the best neuroanatomical indicator ofcognitive decline in the disease. Basal forebrain cholinergic neurons(BFCN) are a subpopulation of neurons that seem to be particularlyvulnerable to the pathology of AD. Dysfunctional atrophy of theseneurons, which in turn results in severe loss of cortical andhippocampal innervation, may be the source for the malfunction of thecholinergic system in AD (Bartus R T Exp Neurol 2000; 163:495-529). Thesevere cortical cholinergic deficits in the disease also include a lossof choline acetyltransferase (ChAT) and acetylcholinesterase (AChE)activity. The basal forebrain cholinergic system is dependent on NGF andcholinergic basal forebrain neurons are the major cell group thatexpresses the receptor for NGF, i.e. TrkA. Although the role of NGF incholinergic neuronal survival and function is well established, studieshave also shown neuroprotective/neurorestorative effects mediated bythis system, e.g. that axotomized cholinergic projections in animals canbe rescued by TrkA activation (Lucidi-Phillipi C A, Neuron., 1996,16(3):653-663).

An early morphological change in the brain of AD-patients is a decreasedhippocampal volume. BDNF/TrkB-stimulated signalling has previously beenshown to be necessary for survival and morphogenesis of especiallyhippocampal neurons. Moreover, it is widely accepted that BDNF plays acritical role in neuronal plasticity and long-term potentiation (LTP).Indeed, a growing body of experimental evidence suggests that increasedBDNF signalling could potentially improve cognition in AD. Thetransplantation of stem cells into the brain of a triple-transgenicmouse model of AD, that expresses amyloid and tau pathology, i.e. themajor neuropathological hallmarks of AD, results in improved cognition(Blurton-Jones M, PNAS, 2009. 106(32): p. 13594-13599). This effect ismediated by BDNF as gain-of-function studies show that recombinant BDNFmimics the beneficial effects of neural stem cell (NSC) transplantation.Furthermore, loss-of-function studies show that depletion of NSC-derivedBDNF fails to improve cognition or restore hippocampal synaptic density.

Given the potent neuroprotective and neurorestorative effects of theTrkA/NGF and TrkB/BDNF systems, small molecule positive modulators ofneurotrophin signalling might be beneficial in treating a number ofdiseases with neurodegeneration including, but not limited to,Alzheimer's disease, Lewy body dementia, frontotemporal dementia, HIVdementia, Huntington's disease, amyotrophic lateral sclerosis and othermotor neuron diseases, Rett syndrome, epilepsy, Parkinson's disease andother parkinsonian disorders. The modulators can also be used in thetreatment of diseases where enhancement of nerve regeneration isbeneficial, such as demyelinating diseases including, but not limitedto, multiple sclerosis. The modulators could also be used forneuroprotection before or after an insult such as spinal cord injury,stroke, hypoxia, ischemia, brain injury including traumatic braininjury. Moreover, the important role of these neurotrophin systems insynaptic plasticity is thought to mediate learning and memory processes,and indicates that the modulators could also be used in disorders wherecognitive function is impaired, including, but not limited to, mildcognitive impairment, dementia disorders (including dementia of mixedvascular and degenerative origin, presenile dementia, senile dementiaand dementia associated with Parkinson's disease, progressivesupranuclear palsy or corticobasal degeneration) and cognitivedysfunction in schizophrenia.

Recent data have also indicated that NGF/TrkA and BDNF/TrkB systems mayoperate as metabotrophins, that is, be involved in the maintenance ofcardiometabolic homeostasis (glucose and lipid metabolism as well asenergy balance, cardioprotection, and wound healing) (Chaldakov G, ArchItal Biol. 2011 June 149(2):257-63). In fact, mutations in the genesencoding BDNF and its receptor TrkB have been shown to lead to severeobesity in humans (Yeo, G S. et al. Nat. Neurosci. 2004, 7, 1187-1189).Therefore, indications such as atherosclerosis, obesity, diabetes andmetabolic syndrome could also benefit from NGF/TrkA and BDNF/TrkBdirected therapies.

Another area of interest when it comes to neurotrophin signalling isneuropsychiatric disorders (Castrén E et al., Neurobiol Dis. 2016 Jul.15, 30169-3). Studies have, for example, clearly demonstrated thatdepressed patients have reduced serum BDNF levels, which are restoredafter successful recovery (Shimizu et al., 2003, Sen et al., 2008).Moreover, several studies have demonstrated that chronic treatment withvarious antidepressant drugs increase BDNF mRNA and protein levels inthe cerebral cortex and hippocampus (Calabrese et al.,Psychopharmacology, 2011, 215, pp. 267-275). Also, local administrationof BDNF into the brain has been shown to reduce depression-like behaviorand mimic the effects of antidepressants (Hoshaw et al., Brain Res.,2005, 1037, pp. 204-208). Notably, the role for BDNF does not seem to berestricted to depression; it has also been implicated in otherdisorders, such as anxiety and schizophrenia (Castrén E., Handb. Exp.Pharmacol., 2014, 220, pp. 461-479). These data suggest that therapiestargeting neurotrophin systems e.g. NGF/TrkA and BDNF/TrkB could have atherapeutic effect in several neuropsychiatric disorders, including, butnot limited to, depression, schizophrenia and anxiety.

The finding that NGF and BDNF play important roles in neuronalhomeostasis in combination with their neuroprotective andneurorestorative effect makes these pathways highly suitable ascandidates for drug intervention for the treatment of diseases of thecentral nervous system and the peripheral nervous system. However, BDNFand NGF are themselves not ideal drug candidates due to theirpharmacokinetic properties, the difficulties in administration and theirlimited ability to cross the blood-brain barrier. This has led toseveral attempts to identify peptides, cyclized peptides, peptidemimetics, small molecule agonist or selective modulators of NGF or BDNF.Several natural products such as gambogic amide (and analogues thereof),deoxygedunin and 7,8-dihydroxyflavone have been demonstrated to act asTrkA or TrkB agonists. Moreover, the tricyclic depressant amitriptylinehas also been shown to be a TrkA and TrkB agonist. However, there iscurrently no specific TrkA or TrkB agonist that has reached the market.Therefore, there is an unmet need in the art for small moleculecompounds that have the ability to stimulate or modulate TrkA and/orTrkB receptors, in combination with TrkC, FGFR1 and/or IGF1R andoptionally other receptor tyrosine kinases for the treatment of bothneurological and non-neurological disorders. There is still a need forcompounds that have an improved potency and improved selectivity to TrkAand/or TrkB receptor.

BDNF production can be affected by a polymorphism within the BDNF gene(rs6265) causes a valine (Val) to methionine (Met) substitution at codon66 (Val66Met). This polymorphism is found in approximately 30% ofCaucasians and up to 70% in Asian populations. The presence of one ortwo Met alleles is associated with lower BDNF production in a subject.This lower BDNF production can lead to increased cognitive decline anddecreased hippocampal volume.

A study by Boots et al (Neurology, 2017, 88, 1-9) demonstrated thatsubjects suffering sporadic Alzheimer's disease who carry the BDNF Metallele experience a steeper decline in episodic memory and executivefunction than non-carriers. Greater memory decline and decreasedhippocampal function have also been observed in Val66Met patients withfamilial Alzheimer's disease (Lim et al., Brain, 2016, 139(10),2766-2777). The same study also showed increased tau-protein andphosphorylated tau-protein in the cerebrospinal fluid in this patientgroup. The decline in memory in subjects with pre-clinical or clinicalAlzheimer's disease was exacerbated by greater amyloid plaque burden,thus suggesting that it is possible to treat Alzheimer's disease atvarious stages of the disease by potentiating the effects of BDNF inpatients with the Val66Met polymorphism. Such treatment may lead toneuroprotection and increased cognitive function.

In general therefore, there remains a need for alternative and/or moreeffective compounds that are useful in the treatment and/or preventionof diseases characterised by impaired signalling of neurotrophins and/orother trophic factors, and in particular neurodegenerative diseases suchas Alzheimer's disease.

Toltrazuril(1-methyl-3-(3-methyl-4-{4-[(trifluoromethyl)sulfanyl]phenoxy}phenyl)-1,3,5-triazinane-2,4,6-trione;Baycox®) is a triazine-based antiprotozoal compounds that are used inveterinary medicine to treat coccidial infections, such as isosporiasis,toxoplasmosis, neosporosis, and equine protozoal meningoencephalitis.

A recent study by Suzuki et al. (FEBS Open Bio 2016, 6 461-468),reported that toltrazuril inhibits the binding of β-amyloid oligomers toephrin type-B receptor 2 (EphB2; a receptor understood to play a rolememory and learning functions) by 30%. However, due to a lack ofselectivity at this receptor, it was not selected for further studies asa potential candidate compound for the treatment of Alzheimer's disease.

Other phenyl-1,3,5-triazine derivatives are disclosed for similar use inveterinary medicine in several old patent documents, such as U.S. Pat.No. 3,933,814, SE 402 103, DE 3 408 768 A1, EP 0 081 142 A2 and 279 219A1. There is no suggestion that any of the compounds that are disclosedin any of these documents may be used to treat human patients per se andcertainly not that the compounds may be useful in the treatment and/orprevention of diseases characterised by impaired signalling ofneurotrophins and/or other trophic factors, such as Alzheimer's disease.

It has now surprisingly been found that certain 4-substitutedphenyl-1,3,5-triazine derivatives are positive modulators of Trkreceptors (including TrkA, TrkB and TrkC) and receptor tyrosine kinasessuch as IGF1R and/or FGFR1, and thus have properties rendering themuseful for the treatment of diseases characterised by impairedsignalling of neurotrophins and/or other trophic factors, such asAlzheimer's disease. As a result of their mode of action, the compoundsare thought to be particularly suitable as therapeutic agents for use indisorders such as Alzheimer's disease, for example in patients havingthe Val66Met mutation in the brain-derived neurotrophic factor (BDNF)gene.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, there is provided a compound of formula I,

wherein:

R¹ represents methyl; phenyl, optionally substituted by one or more G¹groups; or a 5- to 9-membered heteroaryl group, optionally substitutedby one or more G² groups;

G¹ represents halo; phenyl, optionally substituted by one or more G^(a1)groups; phenoxy, optionally substituted by one or more G^(a2) groups;cyano; —N(R^(a1))R^(a2); —C(O)N(R)R^(a4), a 4- to 7-memberedheterocyclyl ring, optionally substituted by one or more G^(a3) groups;a 5- to 6-membered heteroaryl group, optionally substituted by one ormore G^(a4) groups; a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group, whichlatter two groups are optionally substituted by one or more fluoroatoms; or any two G¹ groups may be joined together to form a 5- to6-membered heterocyclyl ring, which may be optionally substituted by oneor more G⁸ groups;

G² represents halo; phenyl, optionally substituted by one or more G^(a6)groups; phenoxy, optionally substituted by one or more G^(a7) groups;cyano; —N(R^(a5))R^(a6); —C(O)N(R^(a7))R^(a8); a 4- to 7-memberedheterocyclyl ring, optionally substituted by one or more G⁰ groups; aC₁₋₄ alkyl group or a C₁₋₄ alkoxy group, which latter two groups areoptionally substituted by one or more fluoro groups;

n represents 0, 1 or 2;

R² represents halo; cyano; —N(R^(a9))R^(a10); a 4- to 7-memberedheterocyclyl ring, optionally substituted by one or more G^(a9) groups;or a phenyl group, optionally substituted by one or more G^(a10) groups,which latter two groups (i.e. the optionally substituted 4- to7-membered heterocyclyl ring and the optionally substituted phenylgroup) are optionally linked to the relevant phenyl group in thecompound of formula I via an O atom; or a C₁₋₆ alkyl group, a C₁₋₆alkoxy group or a —S(O)_(q)C₁₋₆ alkyl group which latter three groupsare optionally substituted by one or more fluoro, ═O, hydroxy, C₁₋₂alkoxy or —N(R^(a11))R^(a12) groups, and/or are optionally substitutedby a 4- to 7-membered heterocyclyl ring, optionally substituted by oneor more G^(a11) groups; or a phenyl group, optionally substituted by oneor more G^(a12) groups;

q represents 0, 1 or 2;

Q represents —N— or —CH—;

X represents —C(R⁴)R⁵—, —O—, —S— or —N(R⁶)—;

m represents 0 or 1;

L represents —C(R⁷)R⁸;

p represents 0 to 1;

R³ represents halo; hydroxy; cyano; or C₁₋₄ alkyl or C₁₋₄ alkoxy,wherein each alkyl group or alkoxy group is optionally substituted byone or more fluoro groups;

R⁴, R⁵, R⁶, R⁷ and R⁸ each independently represent H or C₁₋₂ alkyl;

R^(a1), R^(a2), R^(a3), R^(a4), R^(a5), R^(a6), R^(a7), R^(a8), R^(a9),R^(a10), R^(a11) and R^(a12) each independently represent H or C₁₋₃alkyl; or

R^(a1) and R^(a2), R^(a3) and R^(a4), R^(a5) and R^(a6), R^(a7) andR^(a8), R^(a9) and R^(a10) and R^(a11) and R^(a12) may independently bejoined together to form, together with the atom to which they areattached, a 4- to 7-membered heterocyclyl ring;

G^(a1), G^(a2), G^(a4), G^(a6), G^(a7), G^(a10) and G^(a12) eachindependently represent C₁₋₂ alkyl or halo;

G^(a3), G^(a5), G^(a8), G^(a9) and G^(a11) each independently representC₁₋₂ alkyl, halo or ═O;

and wherein an R² group may also be joined together with any one of R⁴,R⁵, R⁶, R⁷ or R⁸ to form a 4- to 7-membered heterocyclyl ring, or a 5-to 6-membered heteroaryl ring, wherein said heterocyclyl or heteroarylrings are optionally substituted by one or more substituents selectedfrom G³; and

G³ represents halo, C₁₋₂ alkyl or C₁₋₂ alkoxy;

or a pharmaceutically acceptable salt thereof, for use in a method forthe treatment and/or prevention of a disease characterised by impairedsignalling of neurotrophins and/or other trophic factors.

Compounds of formula I that maybe mentioned include those in which G¹represents halo; phenyl, optionally substituted by one or more G^(a1)groups; phenoxy, optionally substituted by one or more G^(a2) groups;cyano; —N(R^(a1))R^(a2); —C(O)N(R^(a3))R^(a4), a 4- to 7-memberedheterocyclyl ring, optionally substituted by one or more G^(a3) groups;a 5- to 6-membered heteroaryl group, optionally substituted by one ormore G^(a4) groups; a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group, whichlatter two groups are optionally substituted by one or more fluoroatoms; or any two G¹ groups may be joined together to form a 5- to6-membered heterocyclyl ring, which may be optionally substituted by oneor more G^(a) groups;

G^(a1), G^(a2) and G^(a4) each independently represent methyl, ethyl,fluoro or chloro; and

G^(a3) and G^(a5) each independently represent methyl, ethyl, fluoro,chloro or ═O.

Further compounds of formula I that may be mentioned include those inwhich G¹ represents halo; phenyl; phenoxy; cyano; —N(R^(a1))R^(a2); a 4-to 7-membered heterocyclyl ring; a C₁₋₄ alkyl group or a C₁₋₄ alkoxygroup, which latter two groups are optionally substituted by one or morefluoro atoms; or any two G¹ groups may be joined together to form a 5-to 6-membered heterocyclyl ring.

Compounds of formula I that may be mentioned include those in which G²represents halo; phenyl, optionally substituted by one or more G^(a6)groups; phenoxy, optionally substituted by one or more G^(a7) groups;cyano; —N(R^(a5))R^(a6); —C(O)N(R^(a7))R^(a8); a 4- to 7-memberedheterocyclyl ring, optionally substituted by one or more G^(a8) groups;a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group, which latter two groups areoptionally substituted by one or more fluoro groups;

G^(a6), G^(a7) and G^(a4) each independently represent methyl, ethyl,fluoro or chloro; and

G^(a8) represents methyl, ethyl, fluoro, chloro or ═O.

Further particular compounds of formula I that may be mentioned includethose in which G² represents halo; phenyl; phenoxy; cyano;—N(R^(a3))R^(a4); a 4- to 7-membered heterocyclyl ring; a C₁₋₄ alkylgroup or a C₁₋₄ alkoxy group, which latter two groups are optionallysubstituted by one or more fluoro groups.

Compounds of the invention that may be mentioned include those in whichR² represents halo; cyano; —N(R^(a9))R^(a10); a 4- to 7-memberedheterocyclyl ring, optionally substituted by one or more G^(a9) groups;or a phenyl group, optionally substituted by one or more G^(a10) groups,which latter two groups (i.e. the optionally substituted 4- to7-membered heterocyclyl ring and the optionally substituted phenylgroup) are optionally linked to the relevant phenyl group in thecompound of formula I via an O atom; or a C₁₋₆ alkyl group, a C₁₋₆alkoxy group or a —S(O)_(q)C₁₋₆ alkyl group which latter three groupsare optionally substituted by one or more fluoro, ═O, hydroxy, C₁₋₂alkoxy or —N(R^(a11))R^(a12) groups, and/or are optionally substitutedby a 4- to 7-membered heterocyclyl ring, optionally substituted by oneor more G^(a11) groups; or a phenyl group, optionally substituted by oneor more G^(a12) groups;

G^(a9), and G^(a11) each independently represent methyl, ethyl, fluoroor chloro or ═O; and

G^(a10) and G^(a12) each independently represent methyl, ethyl, fluoro,chloro.

q represents 0 or 2.

Compounds of the invention that may be mentioned include those in whichR² represents halo; cyano; —N(R^(a9))R^(a10); a 4- to 7-memberedheterocyclyl ring, optionally substituted by one or more G^(a9) groups;or a phenyl group, optionally substituted by one or more G^(a10) groups,which latter two groups (i.e. the optionally substituted 4- to7-membered heterocyclyl ring and the optionally substituted phenylgroup) are optionally linked to the relevant phenyl group in thecompound of formula I via an O atom; or a C₁₋₆ alkyl group, or a C₁₋₆alkoxy group, which latter two groups are optionally substituted by oneor more fluoro, ═O, hydroxy, C₁₋₂ alkoxy or —N(R^(a11))R^(a12) groups,and/or are optionally substituted by a 4- to 7-membered heterocyclylring, optionally substituted by one or more G^(a11) groups; or a phenylgroup, optionally substituted by one or more G^(a12) groups; and

G^(a9), and G^(a11) each independently represent methyl, ethyl, fluoroor chloro or ═O; and

G^(a10) and G^(a12) each independently represent methyl, ethyl, fluoro,chloro.

More particular compounds of formula I that may be mentioned includethose in which R² represents halo; cyano; —N(R)R^(a10); a 4- to7-membered heterocyclyl ring or a phenyl group, which latter two groupsare optionally linked to the relevant phenyl group in the compound offormula I via an O atom; or a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group,which latter two groups are optionally substituted by one or morefluoro, ═O, hydroxy, C₁₋₂ alkoxy or —N(R^(a11))R^(a12) groups, and/orare optionally substituted by a 4- to 7-membered heterocyclyl ring or aphenyl group.

Compounds of formula I that may be mentioned include those in which Qrepresents —CH—.

For the avoidance of doubt, when Q represents —CH—, the position may besubstituted by an R² group as defined herein (i.e. Q may represent —CH—or —CR²—).

Other compounds of formula I that may be mentioned include those inwhich Q represents —N—.

There is further provided a compound of formula I, wherein the compoundof formula I is a compound of formula Ia,

wherein:

R¹ represents methyl; phenyl, optionally substituted by one or more G¹groups; or a 5- to 9-membered heteroaryl group, optionally substitutedby one or more G² groups;

G¹ represents halo; phenyl; phenoxy; cyano; —N(R^(a1))R^(a2); a 4- to7-membered heterocyclyl ring; a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group,which latter two groups are optionally substituted by one or more fluoroatoms; or any two G¹ groups may be joined together to form a 5- to6-membered heterocyclyl ring;

G² represents halo; phenyl; phenoxy; cyano; —N(R^(a5))R^(a6); a 4- to7-membered heterocyclyl ring; a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group,which latter two groups are optionally substituted by one or more fluorogroups;

n represents 0, 1 or 2;

R² represents halo; cyano; —N(R)R^(a10); a 4- to 7-membered heterocyclylring or a phenyl group, which latter two groups are optionally linked tothe relevant phenyl group in the compound of formula I via an O atom; aC₁₋₆ alkyl group or a C₁₋₆ alkoxy group, which latter two groups areoptionally substituted by one or more fluoro, ═O, hydroxy, C₁₋₂ alkoxyor —N(R^(a11))R^(a12) groups, and/or are optionally substituted by a 4-to 7-membered heterocyclyl ring, or a phenyl group;

X represents —C(R⁴)R⁵—, —O—, —S— or —N(R⁶)—;

m represents 0 or 1;

L represents —C(R⁷)R⁸—;

p represents 0 to 1;

R³ represents halo; hydroxy; cyano; or C₁₋₄ alkyl or C₁₋₄ alkoxy,wherein each alkyl group or alkoxy group is optionally substituted byone or more fluoro groups;

R⁴, R⁵, R⁶, R⁷ and R⁸ each independently represent H or C₁₋₂ alkyl;

R^(a1), R^(a2), R^(a5), R^(a6), R^(a9), R^(a10), R^(a11) and R^(a12)each independently represent H or C₁₋₃ alkyl; or

R^(a1) and R^(a2), R^(a5) and R^(a6), R^(a9) and R^(a10), and R^(a11)and R^(a12) may independently be joined together to form, together withthe atom to which they are attached, a 4- to 7-membered heterocyclylring;

and wherein an R² group may also be joined together with any one of R⁴,R⁵, R⁶, R⁷ or R⁸ to form a 4- to 7-membered (preferably 5- to6-membered) heterocyclyl ring, or a 5- to 6-membered (preferably5-membered) heteroaryl ring, wherein said heterocyclyl or heteroarylrings are optionally substituted by one or more substituents selectedfrom G³; and

G³ represents halo, C₁₋₂ alkyl or C₁₋₂ alkoxy,

or a pharmaceutically acceptable salt thereof,

and optionally one or more pharmaceutically-acceptable excipient, suchas an adjuvant, diluent or carrier.

Compounds of formula I, including compounds of formula Ia, that may alsobe mentioned include those in which:

R² represents halo; cyano; —N(R^(a9))R^(a10); a 4- to 7-memberedheterocyclyl ring or a phenyl group, which latter two groups areoptionally linked to the relevant phenyl group in the compound offormula I via an O atom; a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group,which latter two groups are optionally substituted by one or morefluoro, ═O, hydroxy or C₁₋₂ alkoxy groups, and/or are optionallysubstituted by a 4- to 7-membered heterocyclyl ring, or a phenyl group;and

R^(a1), R^(a2), R^(a5), R^(a6), R^(a9) and R^(a10) each independentlyrepresent H or C₁₋₃ alkyl;

or

R^(a1) and R^(a2), R^(a5) and R^(a6), and R^(a9) and R^(a10) mayindependently be joined together to form, together with the atom towhich they are attached, a 4- to 7-membered heterocyclyl ring, or apharmaceutically acceptable salt thereof, for use in a method for thetreatment and/or prevention of a disease characterised by impairedsignalling of neurotrophins and/or other trophic factors.

For the avoidance of doubt, the skilled person will understand thatwhere a particular group is depicted herein as being bound to a ringsystem via a floating bond (i.e. a bond not shown as being bound to aparticular atom within the ring), the relevant group may be bound to anysuitable atom within the relevant ring system (i.e. the ring withinwhich the floating bond terminates).

The skilled person will understand that when an R² group is joinedtogether with any one of R⁴, R⁵, R⁶, R⁷ or R⁸ to form a 4- to 7-memberedheterocyclic ring or a 5- to 6-membered heteroaryl ring, said ring willbe fused to the benzene ring to which R² is attached (i.e. theheteroaryl or heterocyclyl ring in combination with the benzene ringconstitutes an 8- to 11-membered (e.g. 9-membered) heteroaryl group).

There is further provided a compound of formula I, including a compoundof formula Ia, as hereinbefore defined, or a pharmaceutically acceptablesalt thereof, provided that, when R¹ represents methyl, m is 0, and:

-   -   (i) X represents O or S, then n and p do not both represent 0;    -   (ii) when X represents 0, and        -   R² represents a single fluoro group in the 3-position            relative to the triazine ring, then R³ does not represent a            single —CF₃ group in the 4-position relative to the point of            attachment of the benzene ring;        -   R² represents two chloro groups in the 3- and 5-positions            relative to the triazine ring, then R³ does not represent a            single —OCF₃ or cyano group in the 4-position relative to            the point of attachment of the benzene ring;        -   R² represents a single chloro group in the 3-position            relative to the triazine ring, then either            -   (a) p does not represent 0 or,            -   (b) when p represents 1, then R³ does not represent a                chloro group in the 4-position relative to the point of                attachment of the benzene ring; and        -   when n represents 0, then R³ does not represent a single            fluoro, chloro, —CF₃, cyano or methyl group in the            4-position, or a chloro group in the 3-position, relative to            the point of attachment of the benzene ring; and    -   (iii) when X represents S, and        -   R² represents two chloro atoms in the 3- and 5-positions            relative to the triazine ring, then R³ does not represent a            single ethyl group in the 2-position, a single ethoxy group            in the 3- or in the 4-position, or a single chloro, bromo,            cyano, —CF₃, or tert-butyl, group in the 4-position relative            to the point of attachment of the benzene ring;        -   R² represents two methyl groups in the 3- and 5-positions            relative to the triazine ring, then R³ does not represent a            single chloro or bromo group in the 4-position relative to            the point of attachment of the benzene ring;        -   R² represents two methyl groups in the 2- and 5-positions            relative to the triazine ring, then R³ does not represent a            single methyl or tert-butyl group in the 4-position relative            to the point of attachment of the benzene ring; and        -   n represents 0, then R³ does not represent a single chloro,            methyl, cyano or tert-butyl group in the 4-position relative            to the point of attachment of the benzene ring.

There is further provided a compound of formula I, including a compoundof formula Ia, as hereinbefore defined, or a pharmaceutically acceptablesalt thereof, provided that, when

R¹ represents methyl, m is 0, and:

-   -   (iv) X represents O or S, then n and p do not both represent 0;    -   (v) when X represents 0, and        -   R² represents a single fluoro group in the 3-position            relative to the triazine ring, then R³ does not represent a            single —CF₃ group in the 4-position relative to the point of            attachment of the benzene ring;        -   R² represents two chloro groups in the 3- and 5-positions            relative to the triazine ring, then R³ does not represent a            single —OCF₃ group in the 4-position relative to the point            of attachment of the benzene ring;        -   R² represents a single chloro group in the 3-position            relative to the triazine ring, then either            -   (c) p does not represent 0 or,            -   (d) when p represents 1, then R³ does not represent a                chloro group in the 4-position relative to the point of                attachment of the benzene ring; and        -   when n represents 0, then R³ does not represent a single            fluoro, chloro, —CF₃, cyano or methyl group in the            4-position, or a chloro group in the 3-position, relative to            the point of attachment of the benzene ring; and    -   (vi) when X represents S, and        -   R² represents two chloro atoms in the 3- and 5-positions            relative to the triazine ring, then R³ does not represent a            single ethyl group in the 2-position, a single ethoxy group            in the 3- or in the 4-position, or a single chloro, bromo,            cyano, —CF₃, or tert-butyl, group in the 4-position relative            to the point of attachment of the benzene ring;        -   R² represents two methyl groups in the 3- and 5-positions            relative to the triazine ring, then R³ does not represent a            single chloro or bromo group in the 4-position relative to            the point of attachment of the benzene ring;        -   R² represents two methyl groups in the 2- and 5-positions            relative to the triazine ring, then R³ does not represent a            single methyl or tert-butyl group in the 4-position relative            to the point of attachment of the benzene ring; and        -   n represents 0, then R³ does not represent a single chloro,            methyl, or tert-butyl group in the 4-position relative to            the point of attachment of the benzene ring.

The skilled person will understand that, as used herein, references tothe point of attachment of the benzene ring refer to the point ofattachment of the benzene ring to which the relevant substituent isattached to the relevant essential structural feature defined in thecompound of formula I. In the case of the benzene ring to which R³ isattached, the point of attachment of the benzene ring refers to the atomthrough which it is attached to the X group, or, if present, the Lgroup.

References to the position of an R² substituent relative to the triazinering may be understood to refer to the position of the relevantsubstituent relative to the point of attachment of the benzene ring(i.e. the atom through which the benzene ring is attached) to theessential 1,3,5-triazine-2,4,6-trione ring in the compound of formula I.

Compounds of formula I, including compounds of formula Ia, (includingpharmaceutically acceptable salts thereof) as defined in any of thedefinitions provided hereinbefore are referred to collectivelyhereinafter as “the compounds of the invention”.

Compounds of formula I, including compounds of formula Ia, (i.e. thecompounds of the invention) that may be mentioned include those inwhich, when R¹ represents methyl, then

-   (i) n and p do not both represent 0;-   (ii) when X represents 0, then    -   R³ does not represent a single fluoro, chloro, methyl, cyano,        —CF₃, or —OCF₃ group in the 4-position, or a single chloro group        in the 3-position, relative to the point of attachment of the        benzene ring; or    -   R² does not represent a single chloro group in the 3-position        relative to the triazine ring;-   (iii) when X represents S, then R³ does not represent a single    chloro, bromo, —CF₃, cyano, methyl, ethoxy, or tert-butyl group in    the 4-position, a single ethoxy group in the 3-position, or a single    ethyl group in the 2-position, relative to the point of attachment    of the benzene ring,

or a pharmaceutically acceptable salt thereof.

Certain compounds of the invention may be novel and/or not previouslyused in human medicine, thus, in a further embodiment of the invention,there is provided a compound of formula I, including a compound offormula Ia, as defined herein.

There is further provided a compound of formula I, including a compoundof formula Ia, for use in human medicine and/or as a pharmaceutical.

For the avoidance of doubt, the skilled person will understand thatreferences herein to compounds of particular aspects of the invention(such as any aspect of the invention referring to compounds of formula Ias defined hereinbefore) will include references to all embodiments andparticular features thereof, which embodiments and particular featuresmay be taken in combination to form further embodiments and features ofthe invention.

Unless indicated otherwise, all technical and scientific terms usedherein will have their common meaning as understood by one of ordinaryskill in the art to which this invention pertains.

Pharmaceutically acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound ofthe invention with one or more equivalents of an appropriate acid orbase, optionally in a solvent, or in a medium in which the salt isinsoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo, by freeze-drying or by filtration).Salts may also be prepared using techniques known to those skilled inthe art, such as by exchanging a counter-ion of a compound of theinvention in the form of a salt with another counter-ion, for exampleusing a suitable ion exchange resin.

Particular acid addition salts that may be mentioned include carboxylatesalts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate,heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate,propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate,α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate,phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate,o-acetoxy-benzoate, salicylate, nicotinate, isonicotinate, cinnamate,oxalate, malonate, succinate, suberate, sebacate, fumarate, malate,maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts),halide salts (e.g. chloride, bromide or iodide salts, including HCl, HBrand HI salts and the like), sulphonate salts (e.g. benzenesulphonate,methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate,methanesulphonate, ethanesulphonate, propanesulphonate,hydroxy-ethanesulphonate, 1- or 2-naphthalene-sulphonate or1,5-naphthalene-disulphonate salts) or sulphate, pyrosulphate,bisulphate, sulphite, bisulphite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, andthe like.

Particular base addition salts that may be mentioned include saltsformed with alkali metals (such as Li, Na and K salts), alkaline earthmetals (such as Mg and Ca salts), or other metals (such as Al and Znsalts) organic bases (such as benzathine, ethylenediamine, ethanolamine,diethanolamine, triethanolamine, tromethamine, procaine and lysine) andinorganic bases (such as ammonia and aluminium hydroxide). Moreparticularly, base addition salts that may be mentioned include Mg, Caand, most particularly, K and Na salts.

For the avoidance of doubt, compounds of the invention may exist assolids, and thus the scope of the invention includes all amorphous,crystalline and part crystalline forms thereof, and may also exist asoils. Where compounds of the invention exist in crystalline and partcrystalline forms, such forms may include solvates, which are includedin the scope of the invention.

For the avoidance of doubt, compounds of the invention may also exist insolution (i.e. in solution in a suitable solvent). For example,compounds of the invention may exist in aqueous solution, in which casecompounds of the invention may exist in the form of hydrates thereof.

Compounds of the invention may contain double bonds and, unlessotherwise indicated, may thus exist as E (entgegen) and Z (zusammen)geometric isomers about each individual double bond. Unless otherwisespecified, all such isomers and mixtures thereof are included within thescope of the invention.

Compounds of the invention may also exhibit tautomerism. All tautomericforms and mixtures thereof are included within the scope of theinvention (particularly those of sufficient stability to allow forisolation thereof).

Compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/or diastereoisomerism(i.e. existing in enantiomeric or diastereomeric forms).Diastereoisomers may be separated using conventional techniques, e.g.chromatography or fractional crystallisation. The various stereoisomers(i.e. enantiomers) may be isolated by separation of a racemic or othermixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desiredenantiomer or diastereoisomer may be obtained from appropriate opticallyactive starting materials under conditions which will not causeracemisation or epimerisation (i.e. a ‘chiral pool’ method), by reactionof the appropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution; for example, with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography), or by reaction with anappropriate chiral reagent or chiral catalyst, all of which methods andprocesses may be performed under conditions known to the skilled person.Unless otherwise specified, all stereoisomers and mixtures thereof areincluded within the scope of the invention.

Unless otherwise specified, C_(1-z) alkyl groups, and the alkyl parts ofC_(1-z) alkoxy groups (where, in both cases, z is the upper limit of therange), defined herein may be straight-chain or, when there is asufficient number (i.e. a minimum of two or three, as appropriate) ofcarbon atoms, be branched-chain, and/or cyclic (so forming a C_(3-z)cycloalkyl group). When there is a sufficient number (i.e. a minimum offour) of carbon atoms, such groups may also be part cyclic (so forming aC_(4-z) partial cycloalkyl group). For example, cycloalkyl groups thatmay be mentioned include cyclopropyl, cyclopentyl and cyclohexyl.Similarly, part cyclic alkyl groups (which may also be referred to as“part cycloalkyl” groups) that may be mentioned includecyclopropylmethyl. When there is a sufficient number of carbon atoms,such groups may also be multicyclic (e.g. bicyclic or tricyclic) and/orspirocyclic. For the avoidance of doubt, particular alkyl groups thatmay be mentioned include straight chain (i.e. not branched and/orcyclic) alkyl groups.

For the avoidance of doubt, alkyl and alkoxy as described herein mayalso act as linker groups (i.e. groups joining two or more parts of thecompound as described), in which case such groups may be referred to as“alkylene”, “oxyalkylene”, etc.

For the avoidance of doubt, as used herein, references to heteroatomswill take their normal meaning as understood by one skilled in the art.Particular heteroatoms that may be mentioned include phosphorus,selenium, tellurium, silicon, boron, oxygen, nitrogen and sulfur (e.g.oxygen, nitrogen and sulfur, such as oxygen and nitrogen).

As used herein, the term “heterocyclyl” rings or groups may refer tonon-aromatic monocyclic and polycyclic (e.g. bicyclic) heterocyclicrings or groups (which groups may, where containing a sufficient numberof atoms, also be bridged) in which at least one (e.g. one to four) ofthe atoms in the ring system is other than carbon (i.e. a heteroatom),and in which the total number of atoms in the ring system is between asspecified hereinbefore. Further, such heterocyclyl groups may besaturated, forming a heterocycloalkyl, or unsaturated containing one ormore carbon-carbon or, where possible, carbon-heteroatom orheteroatom-heteroatom double and/or triple bonds, forming for example aC_(2-z) (e.g. C_(4-z)) heterocycloalkenyl (where z is the upper limit ofthe range) or a C_(7-z) heterocycloalkynyl group.

For the avoidance of doubt, the skilled person will understand thatheterocyclyl groups that may form part of compounds of the invention arethose that are chemically obtainable, as known to those skilled in theart. Various heterocyclyl groups will be well-known to those skilled inthe art, such as 7-azabicyclo-[2.2.1]heptanyl,6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl,8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl,2,3-dihydroisothiazolyl, dihydropyranyl, dihydropyridinyl,dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl),dithianyl (including 1,4-dithianyl), dithiolanyl (including1,3-dithiolanyl), imidazolidinyl, imidazolinyl, isothiazolidinyl,morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl,oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl,3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridinyl(such as 1,2,3,4-tetrahydropyridinyl and 1,2,3,6-tetrahydropyridinyl),thietanyl, thiiranyl, thiolanyl, tetrahydrothiopyranyl, thiomorpholinyl,trithianyl (including 1,3,5-trithianyl), tropanyl and the like.

Substituents on heterocyclyl groups may, where appropriate, be locatedon any atom in the ring system including a heteroatom. Further, in thecase where the substituent is another cyclic compound, then the cycliccompound may be attached through a single atom on the heterocyclylgroup, forming a spirocyclic compound. The point of attachment ofheterocyclyl groups may be via any suitable atom in the ring system,including (where appropriate) a further heteroatom (such as a nitrogenatom), or an atom on any fused carbocyclic ring that may be present aspart of the ring system. Heterocyclyl groups may also be in the N- orS-oxidised forms, as known to those skilled in the art.

For the avoidance of doubt, any references to polycyclic (e.g. bicyclicor tricyclic) groups (for example when employed in the context ofheterocyclyl or cycloalkyl groups (e.g. heterocyclyl)) as may beemployed herein will refer to ring systems wherein at least twoscissions would be required to convert such rings into a non-cyclic(i.e. straight or branched) chain, with the minimum number of suchscissions corresponding to the number of rings defined (e.g. the termbicyclic may indicate that a minimum of two scissions would be requiredto convert the rings into a straight chain). For the avoidance of doubt,the term bicyclic (e.g. when employed in the context of alkyl groups)may refer to groups in which the second ring of a two-ring system isformed between two adjacent atoms of the first ring, to groups in whichtwo non-adjacent atoms are linked by an alkyl (which, when linking twomoieties, may be referred to as alkylene) group (optionally containingone or more heteroatoms), which later groups may be referred to asbridged, or to groups in which the second ring is attached to a singleatom, which latter groups may be referred to as spiro compounds.

Particular heterocyclyl groups that may be mentioned include piperidinyl(e.g. piperidin-1-yl), octahydro-1H-isoindolyl (e.g.octahydro-1H-isoindol-2-yl), azetidinyl (e.g. azetidine-1-yl), oxetanyl(e.g. oxetan-3-yl), morpholinyl (e.g. morpholin-4-yl), piperazinyl (e.g.piperazin-1yl or piperazin-4-yl), azepanyl (e.g. azepan-1-yl),imidazolidinyl (e.g. imidazolidine-2-yl), pyrrolidinyl (e.g.pyrrolidine-1yl), and diazepanyl (e.g. 1,4-diazepan-1-yl).

As may be used herein, references to “heteroaryl” (with may also bereferred to as heteroaromatic) rings or groups may refer toheteroaromatic groups containing one or more heteroatoms (such as one ormore heteroatoms selected from oxygen, nitrogen and/or sulfur). Suchheteroaryl groups may comprise one, two, or three rings, of which atleast one is aromatic (which aromatic ring(s) may or may not contain theone or more heteroatom). Substituents on heteroaryl/heteroaromaticgroups may, where appropriate, be located on any suitable atom in thering system, including a heteroatom (e.g. on a suitable N atom).

The point of attachment of heteroaryl/heteroaromatic groups may be viaany atom in the ring system including (where appropriate) a heteroatom.Bicyclic heteroaryl/heteroaromatic groups may comprise a benzene ringfused to one or more further aromatic or non-aromatic heterocyclicrings, in which instances, the point of attachment of the polycyclicheteroaryl/heteroaromatic group may be via any ring including thebenzene ring or the heteroaryl/heteroaromatic or heterocycly ring.

For the avoidance of doubt, the skilled person will understand thatheteroaryl groups that may form part of compounds of the invention arethose that are chemically obtainable, as known to those skilled in theart. Various heteroaryl groups will be well-known to those skilled inthe art, such as pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl,imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl,azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl,quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl,benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl andpurinyl.

For the avoidance of doubt, the oxides of heteroaryl/heteroaromaticgroups are also embraced within the scope of the invention (e.g. theN-oxide).

As stated above, heteroaryl includes polycyclic (e.g. bicyclic) groupsin which one ring is aromatic (and the other may or may not bearomatic). Hence, other heteroaryl groups that may be mentioned includegroups such as benzo[1,3]dioxolyl, benzo[1,4]dioxinyl,dihydrobenzo[d]isothiazole, 3,4-dihydrobenz[1,4]oxazinyl,dihydrobenzothiophenyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl,1,2,3,4-tetrahydroquinolinyl, thiochromanyl and the like.

Aromatic groups may be depicted as cyclic groups comprising therein asuitable number of double bonds to allow for aromaticity.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature). Allisotopes of any particular atom or element as specified herein arecontemplated within the scope of the compounds of the invention. Hence,the compounds of the invention also include deuterated compounds, i.e.compounds of the invention in which one or more hydrogen atoms arereplaced by the hydrogen isotope deuterium.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of the invention may be the same, theactual identities of the respective substituents are not in any wayinterdependent. For example, in the situation in which two or more halogroups are present, those groups may be the same or different (e.g. twochloro groups or a fluoro and a chloro group). Similarly, where two ormore alkyl groups are present, the groups in question may be the same ordifferent in terms of their number of carbon atoms and/or whether theyare linear branched or otherwise.

Also for the avoidance of doubt, when a term such as “4- to 7-membered”is employed herein, this will be understood by the skilled person tomean 4-, 5-, 6- and 7-membered, inclusively. Unless otherwise stated,the same reasoning will apply to other such terms used herein.

Further for the avoidance of doubt, when it is specified that asubstituent is itself optionally substituted by one or more substituents(e.g. phenyl optionally substituted by one or more groups independentlyselected from halo), these substituents where possible may be positionedon the same or different atoms. Such optional substituents may bepresent in any suitable number thereof (e.g. the relevant group may besubstituted with one or more such substituents, such as one suchsubstituent).

For the avoidance of doubt, where groups are referred to herein as beingoptionally substituted it is specifically contemplated that suchoptional substituents may be not present (i.e. references to suchoptional substituents may be removed), in which case the optionallysubstituted group may be referred to as being unsubstituted.

For the avoidance of doubt, the skilled person will appreciate thatcompounds of the invention that are the subject of this inventioninclude those that are obtainable, i.e. those that may be prepared in astable form. That is, compounds of the invention include those that aresufficiently robust to survive isolation, e.g. from a reaction mixture,to a useful degree of purity.

Compounds of the invention that may be mentioned include those in which:

R¹ does not represent methyl, that is R¹ represents phenyl, optionallysubstituted by one or more G¹ groups; or a 5- to 9-membered heteroarylgroup, optionally substituted by one or more G² groups;

n and p do not both represent 0; or

n does not represent 2, that is n represents 0 or 1;

Compounds of the invention that may be mentioned include those in whichR¹ represents phenyl, optionally substituted by one or more G¹ groups.

Compounds of the invention that may be mentioned include those in which,when R¹ represents phenyl, the optional G¹ substituent is one or more(preferably one) of:

-   -   halo (e.g. fluoro or chloro),    -   phenoxy,    -   N(R^(a1))R^(a2), in which R^(a1) and R^(a2) each represent H or        C₁₋₂ alkyl or are preferably joined together to form a        6-membered heterocyclyl group, such as a morpholin-4-yl group;    -   C₁₋₄ alkyl, which latter group is optionally substituted with        one or more fluoro groups or C₁₋₂ alkoxy groups, and/or    -   C₁₋₂ alkoxy, which latter group is optionally substituted with        one or more fluoro groups.

Compounds of the invention that may be mentioned include those in which,when R¹ represents phenyl, the optional G¹ substituent is one or more(preferably one) of:

-   -   halo (e.g. fluoro or chloro),    -   phenoxy,    -   N(R^(a1))R^(a2), in which R^(a1) and R^(a2) each represent H or        C₁₋₂ alkyl or are preferably joined together to form a        6-membered heterocyclyl group, such as a morpholin-4-yl group;    -   —C(O)N(R^(a3))R^(a4), in which R^(a3) and R^(a4) each represent        H or C₁₋₂ alkyl or are joined together to form a 4- to        6-membered (e.g. 4-membered) heterocyclyl group,    -   C₁₋₄ alkyl, which latter group is optionally substituted with        one or more fluoro groups or C₁₋₂ alkoxy groups, and/or    -   C₁₋₂ alkoxy, which latter group is optionally substituted with        one or more fluoro groups.

Compounds of the invention that may be mentioned include those in which,when R¹ represents phenyl, the optional G¹ substituent is one or more(preferably one) of:

-   -   halo (e.g. fluoro or chloro),    -   phenoxy,    -   a 5- to 6-membered heteroaryl group, which group is optionally        substituted by one or more (preferably one) methyl group;    -   N(R^(a1))R^(a2), in which R^(a1) and R^(a2) each represent H or        C₁₋₂ alkyl or are preferably joined together to form a        6-membered heterocyclyl group, such as a morpholin-4-yl group;    -   C₁₋₄ alkyl, which latter group is optionally substituted with        one or more fluoro groups or C₁₋₂ alkoxy groups, and/or    -   C₁₋₂ alkoxy, which latter group is optionally substituted with        one or more fluoro groups.

Compounds of the invention that may be mentioned include those in which,when R represents phenyl, the optional G¹ substituent is one or more(preferably one) of:

-   -   halo (e.g. fluoro or chloro),    -   phenoxy,    -   a 5-membered heteroaryl group selected from pyrrolyl,        imidazolyl, pyrazolyl, thiophenyl and furanyl, each of which may        optionally be substituted by one or more (e.g. one) methyl        groups. Preferably, the 5-membered heteroaryl group is selected        from pyrrolyl, pyrazolyl and, particularly, imidazolyl (e.g.        4-methylimidazol-1-yl).    -   N(R^(a1))R^(a2), in which R^(a1) and R^(a2) each represent H or        C₁₋₂ alkyl or are preferably joined together to form a        6-membered heterocyclyl group, such as a morpholin-4-yl group;    -   —C(O)N(R^(a3))R^(a4), in which R^(a3) and R^(a4) each represent        H or C₁₋₂ alkyl, and preferably both R^(a3) and R^(a4) both        represent methyl,    -   C₁₋₄ alkyl, which latter group is optionally substituted with        one or more fluoro groups or C₁₋₂ alkoxy groups, and/or    -   C₁₋₂ alkoxy, which latter group is optionally substituted with        one or more fluoro groups.

Compounds of the invention that may be mentioned include those in which,when R represents phenyl, two G¹ groups are present and are joinedtogether to form a 5-membered heterocyclyl ring, such as a dioxolanylring.

Compounds of the invention that may be mentioned include those in which:

R¹ represents a pyridinyl, a pyrazolyl, an indolyl, a thiazolyl, abenzofuranyl, or a thiophenyl, group, optionally substituted by one ormore G² groups;

the optional G² substituent is one or more (preferably one) phenyl,halo, C₁₋₂ alkyl or C₁₋₂ alkoxy groups, which latter two groups areoptionally substituted with one or more fluoro groups.

Compounds of the invention that may be mentioned include those in whichn is 0.

Compounds of the invention that may be mentioned include those in whichn is 2 or, preferably, 1.

Compounds of the invention that may be mentioned include those in whichR² represents halo; cyano; —N(R^(a9))R^(a10); a 4- to 7-memberedheterocyclyl ring or a phenyl group, which latter two groups areoptionally linked to the relevant phenyl group in the compound offormula I via an O atom; a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group,which latter two groups are optionally substituted by one or morefluoro, ═O, —N(R¹)R¹² or C₁₋₂ alkoxy groups, and/or are optionallysubstituted by a 4- to 7-membered heterocyclyl ring or a phenyl group.

Compounds of the invention that may be mentioned include those in whichR² represents a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group, which groupsare optionally substituted by one or more ═O or —N(R^(a11))R^(a12)groups.

Particular compounds of the invention that may be mentioned are thosewherein, when present, R^(a11) and R^(a12) are not joined together.

Compounds of the invention that may be mentioned include those in whichR² represents halo; cyano; —N(R^(a9))R^(a10); a 4- to 7-memberedheterocyclyl ring or a phenyl group, which latter two groups areoptionally linked to the relevant phenyl group in the compound offormula I via an O atom; a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group or a—S(O)_(q)C₁₋₆ alkyl group which latter three groups are optionallysubstituted by one or more fluoro, ═O, —N(R^(a11))R^(a12) or C₁₋₂ alkoxygroups, and/or are optionally substituted by a phenyl group or a 4- to7-membered heterocyclyl ring, which 4- to 7-membered heterocyclyl ringmay be optionally substituted by one or more (preferably one) methyl,ethyl, fluoro, chloro or, preferably, ═O group; and

q represents 0 or 2.

Compounds of the invention that may be mentioned include those in whichR² represents halo; cyano; —N(R^(a9))R^(a10); a 4- to 7-memberedheterocyclyl ring or a phenyl group, which latter two groups areoptionally linked to the relevant phenyl group in the compound offormula I via an O atom; a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group,which latter two groups are optionally substituted by one or morefluoro, ═O, —N(R^(a11))R^(a12) or C₁₋₂ alkoxy groups, and/or areoptionally substituted by a phenyl group or a 4- to 7-memberedheterocyclyl ring, which 4- to 7-membered heterocyclyl ring may beoptionally substituted by one or more (preferably one) methyl, ethyl,fluoro, chloro or, preferably, ═O group.

Compounds of the invention that may be mentioned include those in whichR² represents halo; cyano; —N(R^(a9))R^(a10); a 4- to 7-memberedheterocyclyl ring or a phenyl group, which latter two groups areoptionally linked to the relevant phenyl group in the compound offormula I via an O atom; a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group,which latter two groups are optionally substituted by one or more fluoroor C₁₋₂ alkoxy groups, and/or are optionally substituted by a 4- to7-membered heterocyclyl ring or a phenyl group.

Compounds of the invention that may be mentioned include those in which,when n is 1 or 2, R² represents one or more of:

-   -   halo (e.g. bromo or chloro);    -   cyano;    -   linear, branched or cyclic, C₁₋₆ alkyl, optionally substituted        with one or more fluoro, ═O, —N(R^(a11))R^(a12) or C₁₋₂ alkoxy        groups;    -   linear, branched or cyclic, C₁₋₆ alkoxy (which group is, for the        avoidance of doubt, attached to the phenyl ring in a compound of        formula I via the oxygen atom, and the alkyl part of which is        optionally branched and/or cyclic), optionally substituted with        one or more fluoro, ═O, —N(R^(a11))R^(a12) or C₁₋₂ alkoxy        groups, a phenyl group, a 4- or 5-membered heterocyclyl group        (e.g. oxetanyl or oxolanyl).

Compounds of the invention that may be mentioned include those in which,when n is 1 or 2, R² represents one or more of:

-   -   halo (e.g. bromo or chloro);    -   cyano;    -   linear branched or cyclic SC₁₋₆ alkyl, optionally substituted by        one or more one or more fluoro, ═O, —N(R^(a11))R^(a12) or C₁₋₂        alkoxy groups;    -   linear branched or cyclic SO₂C₁₋₆ alkyl, optionally substituted        by one or more one or more fluoro, ═O, —N(R^(a11))R^(a12) or        C₁₋₂ alkoxy groups;    -   linear, branched or cyclic, C₁₋₆ alkyl, optionally substituted        with one or more fluoro, ═O, —N(R^(a11))R^(a12) or C₁₋₂ alkoxy        groups;    -   linear, branched or cyclic, C₁₋₆ alkoxy (which group is, for the        avoidance of doubt, attached to the phenyl ring in a compound of        formula I via the oxygen atom, and the alkyl part of which is        optionally branched and/or cyclic), optionally substituted with        one or more fluoro, ═O, —N(R^(a11))R^(a12) or C₁₋₂ alkoxy        groups, a phenyl group, or a 4- or 5-membered heterocyclyl        group, (e.g. oxetanyl, oxolanyl or imidazolidinone), which 4- or        5-membered heterocyclyl group is optionally substituted by one        (e.g. one) or more fluoro, methyl or ═O groups.

Particular compounds of the invention that may be mentioned includethose in which, when n is 1 or 2, R² represents:

-   -   linear, branched or cyclic, C₁₋₆ alkyl, optionally substituted        with one or more ═O or —N(R^(a11))R^(a12) groups;    -   linear, branched or cyclic, C₁₋₆ alkoxy (which group is, for the        avoidance of doubt, attached to the phenyl ring in a compound of        formula I via the oxygen atom, and the alkyl part of which is        optionally branched and/or cyclic), optionally substituted with        one or more ═O or —N(R^(a11))R^(a12) groups.

Particular compounds of the invention that may be mentioned are thosewherein, when present, R^(a11) and R^(a12) are not joined together.

Compounds of the invention that may be mentioned include those in which,when n is 1 or 2, R² represents one or more of:

-   -   halo (e.g. bromo or chloro);    -   cyano;    -   linear, branched or cyclic, C₁₋₆ alkyl, optionally substituted        with one or more fluoro groups, C₁₋₂ alkoxy groups;    -   linear, branched or cyclic, C₁₋₆ alkoxy (which group is, for the        avoidance of doubt, attached to the phenyl ring in a compound of        formula I via the oxygen atom, and the alkyl part of which is        optionally branched and/or cyclic), optionally substituted with        one or more fluoro groups, C₁₋₂ alkoxy groups, a phenyl group, a        4- or 5-membered heterocyclyl group (e.g. oxetanyl or oxolanyl).

Compounds of the invention that may be mentioned include those in which,when n is 1 or 2, R² represents one or more of:

-   -   halo (e.g. bromo or chloro);    -   cyano;    -   linear, branched or cyclic, C₁₋₆ alkyl, optionally substituted        with one or more fluoro groups, C₁₋₂ alkoxy groups;    -   linear, branched or cyclic, C₁₋₆ alkoxy (which group is, for the        avoidance of doubt, attached to the phenyl ring in a compound of        formula I via the oxygen atom, and the alkyl part of which is        optionally branched and/or cyclic), optionally substituted with        one or more fluoro groups, C₁₋₂ alkoxy groups, a phenyl group or        a 4- or 5-membered heterocyclyl group (e.g. oxetanyl, oxolanyl        or imidazolidinone), which 4- or 5-membered heterocyclyl group        is optionally substituted by one or more fluoro, methyl or ═O        groups.

Compounds of the invention that may be mentioned include those in which,when n is 1 or 2, R² represents one or more of:

-   -   halo (e.g. bromo or chloro);    -   cyano;    -   —SC₁₋₃ alkyl (e.g. SMe);    -   —S(O)₂C₁₋₃ alkyl (e.g. SO₂Me)    -   linear, branched or cyclic, C₁₋₆ alkyl, optionally substituted        with one or more fluoro groups, C₁₋₂ alkoxy groups;    -   linear, branched or cyclic, C₁₋₆ alkoxy (which group is, for the        avoidance of doubt, attached to the phenyl ring in a compound of        formula I via the oxygen atom, and the alkyl part of which is        optionally branched and/or cyclic), optionally substituted with        one or more fluoro groups, C₁₋₂ alkoxy groups, a phenyl group or        a 4- or 5-membered heterocyclyl group (e.g. oxetanyl, oxolanyl        or imidazolidinone), which 4- or 5-membered heterocyclyl group        is optionally substituted by one or more fluoro, methyl or ═O        groups.

Compounds of the invention that may be mentioned include those in whichm is 1.

Compounds of the invention that may be mentioned include those in which,when m is 1:

R⁷ and R⁸ independently represent H or methyl;

X represents —C(R⁴)R⁵—, —N(R⁶)—, —S— or, more preferably —O—.

Compounds of the invention that may be mentioned include those in which,when m is 0 and X represents —N(R⁶)—, R⁶ represents methyl or,preferably, H; or R⁶ may be joined together with an R² group to form a5-membered heteroaryl ring (e.g. indolyl or indazolyl), which ring isoptionally substituted by one or more halo or C₁₋₂ alkyl substituent.

Compounds of the invention that may be mentioned include those in which,when m is 1 and X represents O and L represents —C(R⁷)R⁸—;

R⁸ represents H;

R⁷ is joined together with R² to form, e.g. together along with adjacentcarbon atoms on the benzene ring to which R² is attached in a compoundof formula I, a 5-membered heterocyclyl ring (e.g. a dioxolanyl ring).

Compounds of the invention that may be mentioned include those in whichX represents —C(R⁴)R⁵—, —O— or —N(R⁶)—.

Compounds of the invention that may be mentioned include those in whichm is 0.

Compounds of the invention that may be mentioned include those in which,when m is 0, X represents —S— or, more preferably, —O—.

Compounds of the invention that may be mentioned include those in whichp is 0.

Compounds of the invention that may be mentioned include those in which,when p is 1, R³ represents:

-   -   cyano;    -   halo (e.g. fluoro or, preferably, chloro);    -   C₁₋₂ alkoxy, optionally substituted with one or more fluoro        groups; or    -   linear, branched or cyclic, C₁₋₃ alkyl, optionally substituted        with one or more fluoro groups.

Compounds of the invention that may be mentioned include those in whichR¹ represents phenyl, optionally substituted by a fluoro, a chloro, amethyl, a methoxy, a trifluoromethyl, or a trifluoromethoxy substituentin the 3- or the 4-position relative to the point of attachment of thebenzene ring.

Compounds of the invention that may be mentioned include those in whichR¹ represents a pyridinyl (e.g. pyridin-2-yl), an indolyl (e.g.indol-4-yl or indol-5-yl), a thiazolyl (e.g. 1,3-thiazol-5-yl), abenzofuranyl (e.g. benzofuran-5-yl, benzofuran-4-yl orbenzolfuran-7-yl), or a thiophenyl (e.g. thiophen-2-yl), group, whichthiophenyl group is optionally substituted by a methyl group (e.g. inthe 5-position), or a pyrazolyl group, which pyrazolyl group isoptionally substituted by one or more (e.g. one) phenyl group (e.g.1-phenylpyrazol-4-yl).

Compounds of the invention that may be mentioned include those in whichR¹ represents a pyridinyl (e.g. pyridin-2-yl), an indolyl (e.g.indol-4-yl or indol-5-yl), a thiazolyl (e.g. 1,3-thiazol-5-yl), abenzofuranyl (e.g. benzofuran-5-yl), or a thiophenyl (e.g.thiophen-2-yl), group, which thiophenyl group is optionally substitutedby a methyl group (e.g. in the 5-position).

Compounds of the invention that may be mentioned include those in whichR¹ represents methyl or, preferably, phenyl optionally substituted byone methyl, methoxy, fluoro or chloro group (e.g. phenyl (i.e.unsubstituted), 3- or 4-methylphenyl, 2-,3- or 4-methoxyphenyl, 3- or4-chlorophenyl or 4-fluorophenyl), benzofuran-yl (e.g. benzofuran-5-yl,benzofuran-4-yl or benzofuran-7-yl), indolyl (e.g. indol-4-yl orindol-5-yl) benzodioxyl (e.g. 1,3-benzodiox-5-yl), thiophenyl optionallysubstituted by one or more methyl group (e.g. 5-methylthiophen-2-yl) orpyrazoylyl optionally substituted by one or more phenyl group (e.g.1-phenylpyrazol-4-yl).

Compounds of the invention that may be mentioned include those in whichR¹ represents methyl or, preferably, phenyl optionally substituted byone methyl, methoxy, fluoro or chloro group (e.g. phenyl (i.e.unsubstituted), 3- or 4-methylphenyl, 2-,3- or 4-methoxyphenyl, 3- or4-chlorophenyl or 4-fluorophenyl), benzofuran-yl (e.g. benzofuran-5-yl),indolyl (e.g. indol-4-yl or indol-5-yl) benzodioxyl (e.g.1,3-benzodiox-5-yl), thiophenyl optionally substituted by one or moremethyl group (e.g. 5-methylthiophen-2-yl) or pyrazoylyl optionallysubstituted by one or more phenyl group (e.g. 1-phenylpyrazol-4-yl).

More particular compounds of the invention that may be mentioned includethose in which R¹ represents phenyl, 3-methylphenyl, 4-methylphenyl,3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl or5-methylthiophen-2-yl.

Compounds of the invention that may be mentioned include those in which,when n is 2, R² represents one or more substituents selected from C₁₋₂alkyl and C₁₋₂ alkoxy, both of which are optionally substituted with oneor more fluoro groups.

Compounds of the invention that may be mentioned include those in which,when n is 2, the R² groups are located at the 2- and 5-positions,relative to the triazine ring. In particular compounds that may bementioned, n is 2, the R² groups are positioned at the 2- and5-positions, relative to the triazine ring, and each R² representsmethyl.

Compounds of the invention that may be mentioned include those in whichn is 1.

Compounds of the invention that may be mentioned include those in which,when n is 1, R² represents bromo, linear or branched C₁₋₄ alkyl (e.g.methylorethyl), optionally substituted with one or more fluoro, ═O or—N(R^(a11))R^(a12) groups; or C₁₋₅ alkoxy (e.g. methoxy or ethoxy),optionally substituted with one or more fluoro, ═O or —N(R^(a11))R^(a12)groups, a 4- to 7-membered (e.g. 4- to 5-membered) heterocyclyl ring(forming, for example, an oxetanylmethoxy group e.g. anoxetan-3-ylmethoxy group) or C₁₋₂ alkoxy groups (forming, for example, amethoxyethoxy group).

Particular compounds of the invention that may be mentioned includethose in which, when n is 1, R² represents linear or branched C₁₋₄ alkyl(e.g. methyl or ethyl), optionally substituted with one or more ═O or—N(R^(a11))R¹² groups; or C₁₋₅ alkoxy (e.g. methoxy or ethoxy),optionally substituted with one or more ═O or —N(R^(a11))R¹² groups.

Particular —N(R^(a11))R^(a12) groups that may be mentioned include—N(H)methyl, —N(H)ethyl, —N(methyl)₂, —N(ethyl)₂, —N(n-propyl)₂.Preferably, when present, the —N(R^(a7))R^(a8) group is —N(methyl)₂(i.e. —N(Me)₂ or —N(CH₃)₂).

Particular compounds of the invention that may be mentioned are thosewherein, when present, R^(a11) and R^(a12) are not joined together.

Compounds of the invention that may be mentioned include those in which,when n is 1, R² represents bromo, linear or branched C₁₋₄ alkyl (e.g.methyl), optionally substituted with one or more fluoro groups; or C₁₋₅alkoxy (e.g. methoxy, ethoxy, isopropoxy, cyclopentoxy), optionallysubstituted with one or more fluoro groups, a 4- to 7-membered (e.g. 4-to 5-membered) heterocyclyl ring (forming, for example, anoxetanylmethoxy group e.g. an oxetan-3-ylmethoxy group) or C₁₋₂ alkoxygroups (forming, for example, a methoxyethoxy group).

Compounds of the invention that may be mentioned include those in which,when n is 1 the R² group is located at the 2- or, preferably, the3-position, relative to the triazine ring.

Compounds of the invention that may be mentioned include those in whichR² is joined to R⁶ to form a pyrrole ring (i.e. forming, together withthe benzene ring to which R² is attached, an indole group), said pyrrolering (or indole group) being preferably substituted at the 3-position bya methyl group, and m represents 0.

Particular compounds of the invention that may be mentioned includethose in which, n is 1, R² is located at the 3-position relative to thetriazine ring, and R² represents methyl, methoxy, 2-methoxyethoxy,—OCH₂C(O)N(CH₃)₂ or —CH₂C(O)N(CH₃)₂.

In particular, compounds of the invention that may be mentioned includethose in which, n is 1, R² is located at the 3-position relative to thetriazine ring, and R² represents —OCH₂C(O)N(CH₃)₂ or —CH₂C(O)N(CH₃)₂.

Particular compounds of the invention that may be mentioned includethose in which, n is 1, R² is located at the 3-position relative to thetriazine ring, and R² represents methyl, methoxy or 2-methoxyethoxy.

Compounds of the invention that may be mentioned include those in whichX represents O.

Compounds of the invention that may be mentioned include those in which,when p is 1, R³ represents C₁₋₂ alkyl or C₁₋₂ alkoxy, optionallysubstituted with one or more fluoro groups.

Compounds of the invention that may be mentioned include those in whichm is 0 and/or p is 0.

Compounds of the invention that may be mentioned include those in whichp is 0, or p is 1 and R³ represents methyl. In such compounds R³ maypreferably be in the 2-position relative to the point of attachment ofthe benzene ring.

Compounds of the invention that may be mentioned include those in which:

R¹ represents phenyl optionally substituted by one methyl, methoxy,fluoro or chloro group (e.g. phenyl (i.e. unsubstituted), 3- or4-methylphenyl, 2-,3- or 4-methoxyphenyl, 3- or 4-chlorophenyl or4-fluorophenyl), benzofuran-yl (e.g. benzofuran-5-yl, benzofuran-4-yl orbenzofuran-7-yl), indolyl (e.g. indol-4-yl or indol-5-yl) benzodioxyl(e.g. 1,3-benzodiox-5-yl), thiophenyl optionally substituted by one ormore methyl group (e.g. 5-methylthiophen-2-yl) or pyrazoylyl optionallysubstituted by one or more phenyl group (e.g. 1-phenylpyrazol-4-yl);

n represents 1 and R² represents bromo, linear or branched C₁₋₄ alkyl(e.g. ethyl, or, preferably, methyl), optionally substituted with one ormore fluoro, ═O or —N(R^(a11))R^(a12) groups; or C₁₋₅ alkoxy (e.g.methoxy or ethoxy), optionally substituted with one or more fluoro, ═Oor —N(R^(a11))R^(a12) groups, a 4- to 7-membered (e.g. 4- to 5-membered)heterocyclyl ring (forming, for example, an oxetanylmethoxy group e.g.an oxetan-3-ylmethoxy group) or C₁₋₂ alkoxy groups (forming, forexample, a methoxyethoxy group); or

n represents 2 and each R² represents C₁₋₂ alkyl (e.g. methyl) or C₁₋₂alkoxy (e.g. methoxy), both of which are optionally substituted with oneor more fluoro groups;

Q represents —CH—;

X represents —S—, or, preferably, —O—;

m represents 0; and

p represents 0 or p represents 1 and R³ represents methyl (in suchcompounds, the methyl group is preferably in the 2-position relative tothe point of attachment of the benzene ring.).

Further compounds of the invention that may be mentioned include thosein which:

R¹ represents phenyl optionally substituted by one methyl, methoxy,fluoro or chloro group (e.g. phenyl (i.e. unsubstituted), 3- or4-methylphenyl, 2-,3- or 4-methoxyphenyl, 3- or 4-chlorophenyl or4-fluorophenyl), benzofuran-yl (e.g. benzofuran-5-yl, benzofuran-4-yl orbenzofuran-7-yl), indolyl (e.g. indol-4-yl or indol-5-yl) benzodioxyl(e.g. 1,3-benzodiox-5-yl), thiophenyl optionally substituted by one ormore methyl group (e.g. 5-methylthiophen-2-yl) or pyrazoylyl optionallysubstituted by one or more phenyl group (e.g. 1-phenylpyrazol-4-yl);

n is 1, R² is located at the 3-position relative to the triazine ring,and R² represents methyl, methoxy or 2-methoxyethoxy;

Q represents —CH—;

X represents —O—;

m represents 0; and

p represents 0 or p represents 1 and R³ represents methyl (in suchcompounds, the methyl group is preferably in the 2-position relative tothe point of attachment of the benzene ring).

Other compounds of the invention that may be mentioned include those inwhich:

R¹ represents methyl or, preferably, phenyl optionally substituted byone methyl, methoxy, fluoro or chloro group (e.g. phenyl (i.e.unsubstituted), 3- or 4-methylphenyl, 2-,3- or 4-methoxyphenyl, 3- or4-chlorophenyl or 4-fluorophenyl), benzofuran-yl (e.g. benzofuran-5-yl),indolyl (e.g. indol-4-yl or indol-5-yl) benzodioxyl (e.g.1,3-benzodiox-5-yl), thiophenyl optionally substituted by one or moremethyl group (e.g. 5-methylthiophen-2-yl) or pyrazoylyl optionallysubstituted by one or more phenyl group (e.g. 1-phenylpyrazol-4-yl);

R² is joined to R⁶ to form a pyrrole ring (i.e. forming, together withthe benzene ring to which R² is attached, an indole group), said pyrrolering (or indole group) being preferably substituted at the 3-position bya methyl group;

m represents 0;

Q represents —CH—; and

p represents 1 or, preferably, 0;

Other compounds of the invention that may be mentioned include those inwhich:

R¹ represents methyl;

n represents 1;

R² represents bromo, linear or branched C₁₋₄ alkyl, optionallysubstituted with one or more fluoro groups; or C₁₋₅ alkoxy, optionallysubstituted with one or more fluoro groups, a 4- to 7-memberedheterocyclyl ring or C₁₋₂ alkoxy groups; and

p represents 0 or 1 (preferably 0).

Other compounds of the invention that may be mentioned include those inwhich:

R¹ represents methyl;

n represents 1 and R² is preferably located in the 2, or, morepreferably the 3-position relative to the point of attachment of thebenzene ring;

R² represents bromo, linear or branched C₁₋₄ alkyl, optionallysubstituted with one or more fluoro groups; or C₁₋₅ alkoxy, optionallysubstituted with one or more fluoro groups, a 4- to 7-memberedheterocyclyl ring or C₁₋₂ alkoxy groups; and

p represents 0 or 1 (preferably 0).

Other compounds of the invention that may be mentioned include those inwhich:

R¹ represents methyl;

n represents 1 or 2;

R² represents bromo, linear or branched C₁₋₄ alkyl, optionallysubstituted with one or more fluoro groups; or C₁₋₅ alkoxy, optionallysubstituted with one or more fluoro groups, a 4- to 7-memberedheterocyclyl ring or C₁₋₂ alkoxy groups; and

p represents 0.

Other compounds of the invention that may be mentioned include those inwhich:

R¹ represents methyl;

n represents 1 and R² represents bromo, linear or branched C₁₋₄ alkyl(e.g. ethyl, or, preferably, methyl), optionally substituted with one ormore fluoro, ═O or —N(R^(a11))R^(a12) groups; or C₁₋₅ alkoxy (e.g.methoxy or ethoxy), optionally substituted with one or more fluoro, ═Oor —N(R^(a11))R^(a12) groups, a 4- to 7-membered (e.g. 4- to 5-membered)heterocyclyl ring (forming, for example, an oxetanylmethoxy group e.g.an oxetan-3-ylmethoxy group) or C₁₋₂ alkoxy groups (forming, forexample, a methoxyethoxy group);

Q represents —CH—;

X represents —S—, or, preferably —O—;

m represents 0;

p represents 0 or p represents 1 and R³ represents methyl (in suchcompounds, the methyl group is preferably in the 2-position relative tothe point of attachment of the benzene ring.).

Further compounds of the invention that may be mentioned include thosein which:

R¹ represents methyl;

n is 1, R² is located at the 3-position relative to the triazine ring,and R² represents methyl, methoxy or 2-methoxyethoxy;

Q represents —CH—;

X represents —O—;

m represents 0; and

p represents 0 or p represents 1 and R³ represents methyl (in suchcompounds, the methyl group is preferably in the 2-position relative tothe point of attachment of the benzene ring.) (preferably p represents0).

Particular compounds of the invention that may be mentioned includethose compounds as described in the examples provided herein, andpharmaceutically acceptable salts thereof. For the avoidance of doubt,where such compounds of the invention include compounds in a particularsalt form, compounds of the invention include those compounds innon-salt form and in the form of any pharmaceutically acceptable saltthereof (which may include the salt form present in such examples).

More particular compounds of the invention that may be mentioned includethose described in Examples 5, 9, 11, 16, 24, 27, 35, 40, 41, 43, 45,46, 47, 48, 49, 50, 51, 52, 54, 56, 57, 58, 59, 60, 61, 62, 66, 68, 6972 and 73. Yet more particular compounds of the invention that may bementioned include those described in Examples 5, 11, 41, 56, 57, 58, 59,60, 61, 62, 66, 69, 72 and 73.

Medical Uses

As indicated herein, the compounds of the invention, and thereforecompositions and kits comprising the same, are useful aspharmaceuticals.

Although compounds of the invention may possess pharmacological activityas such, certain pharmaceutically-acceptable (e.g. “protected”)derivatives of compounds of the invention may exist or be prepared whichmay not possess such activity, but may be administered parenterally ororally and thereafter be metabolised in the body to form compounds ofthe invention. Such compounds (which may possess some pharmacologicalactivity, provided that such activity is appreciably lower than that ofthe active compounds to which they are metabolised) may therefore bedescribed as “prodrugs” of compounds of the invention.

As used herein, references to prodrugs will include compounds that forma compound of the invention, in an experimentally-detectable amount,within a predetermined time, following enteral (e.g. oral) or parenteraladministration. All prodrugs of the compounds of the invention areincluded within the scope of the invention.

Furthermore, certain compounds of the invention may possess no orminimal pharmacological activity as such, but may be administeredparenterally or orally, and thereafter be metabolised in the body toform compounds of the invention that possess pharmacological activity assuch. Such compounds (which also includes compounds that may possesssome pharmacological activity, but that activity is appreciably lowerthan that of the active compounds of the invention to which they aremetabolised), may also be described as “prodrugs”.

For the avoidance of doubt, compounds of the invention are thereforeuseful because they possess pharmacological activity, and/or aremetabolised in the body following oral or parenteral administration toform compounds that possess pharmacological activity.

As described herein, compounds of the invention may be particularlyuseful in the treatment of diseases characterised by impaired signallingof neurotrophins and/or other trophic factors. Due to their mode ofaction, the compounds of the invention may have particular utility inthe treatment of such diseases in patients with the Val66Met mutation inthe BDNF gene.

The compounds of the invention may also have particular utility in thetreatment of diseases characterised by impaired signalling ofneurotrophins and/or other trophic factors in patients having othergenetic variations, including deletions, that directly or indirectlyaffect the BDNF gene. For example, the compounds of the invention mayhave particular utility in treating diseases in patients having thers12291063 minor C allele, which is known to be associated with lowerBDNF expression, and/or in patients having the deletions associated withWAGR syndrome, such as the deletions in chromosome 11.

Accordingly, in particular embodiments of the invention, there isprovided the compounds of the invention for use in the treatment of thediseases described herein in a patient having the Val66Met mutation inthe BDNF gene, and/or in a patient having the rs12291063 minor C allele,and/or in a patient having the genetic deletions associated with WAGRsyndrome.

The skilled person will understand that trophic factors refer to a classof molecules that promote the growth and maintenance of cellulartissues. Neurotrophins may be understood to refer to a class ofmolecules associated with promoting the growth and survival of neurons,which are also referred to as neurotrophic factors. Examples ofneurotrophins include NGF, BDNF, NT3 and NT4/5. Other trophic factorsinclude insulin-like growth factor (IGF-1), fibroblast growth factors(FGFs), hepatocyte growth factor (HGF) and glial cell line-derivedneurotrophic factors such as glial cell-derived neurotrophic factor(GDNF), Neurturin (NRTN), artemin (ARTN) and persephin (PSPN).

As used herein, the phrase diseases characterised by impaired signallingof neurotrophins and other trophic factors may be understood to indicatediseases and disorders that involve reduced signalling of trophicfactors, such as those listed above. Such disorders may be treatedthrough the positive modulation of neurotrophin receptors, such as TrKA,TrKB and TrkC and/or their signalling, and receptor tyrosine kinasessuch as FGFR1 and IGF1R and/or their signalling and/or the positivemodulation of other trophic factor receptors.

The Val66Met mutation in the BDNF gene refers to a commonsingle-nucleotide polymorphism in the brain-derived neurotrophic factor(BDNF) gene, resulting in a methionine (Met) substitution for valine(Val) at codon 66 (Val66Met).

The skilled person will understand that references to the treatment of aparticular condition (or, similarly, to treating that condition) willtake their normal meanings in the field of medicine. In particular, theterms may refer to achieving a reduction in the severity and/orfrequency of occurrence of one or more clinical symptom associated withthe condition, as adjudged by a physician attending a patient having orbeing susceptible to such symptoms. For example, in the case ofAlzheimer's disease, the term may refer to achieving an improvement incognition in the patient being treated.

As used herein, the term prevention (and, similarly, preventing) willinclude references to the prophylaxis of the disease or disorder (andvice versa). As such, references to prevention may also be references toprophylaxis, and vice versa. In particular, such terms may refer toachieving a reduction (for example, at least a 10% reduction, such as atleast a 20%, 30% or 40% reduction, e.g. at least a 50% reduction) in thelikelihood of the patient (or healthy subject) developing the condition(which may be understood as meaning that the condition of the patientchanges such that patient is diagnosed by a physician as having, e.g.requiring treatment for, the relevant disease or disorder).

As used herein, references to a patient (or to patients) will refer to aliving subject being treated, including mammalian (e.g. human) patients.In particular, a “pharmaceutical composition” is intended to refer to acomposition that is intended to for use to treat human patients in humanmedicine. Similarly, compounds or compositions for use aspharmaceuticals are intended to be used in the treatment of humanpatients. In this respect, and in general, references to a patient willrefer to human patients.

For the avoidance of doubt, the skilled person will understand that suchtreatment or prevention will be performed in a patient (or subject) inneed thereof. The need of a patient (or subject) for such treatment orprevention may be assessed by those skilled the art using routinetechniques.

As used herein, the terms disease and disorder (and, similarly, theterms condition, illness, medical problem, and the like) may be usedinterchangeably.

Compounds of the invention are modulators of neurotrophin receptors,such as TrkA, TrkB, TrkC and/or their signalling and receptor tyrosinekinases, such as FGFR1 and IGF1R and/or their signalling. The compoundsare believed to have an improved potency for the modulation ofneurotrophin receptors, such as TrkA, TrkB, TrkC and/or their signallingand receptor tyrosine kinases, such as FGFR1 and IGF1R and/or theirsignalling. It is believed that the compounds of the invention wouldhave a reduced potential for side effects associated with conventionalagonists for TrkA and TrkB.

Another indication includes setting in which there is a goal forenhancing plasticity of the nervous system, such as duringrehabilitation or acquisition of a new learned physical or intellectualskill. Moreover, it also includes facilitation of neuronal ornon-neuronal or stem cell survival or promoting neural function bytreating a neural or non-neuronal or stem cell with a compound of theinvention having the ability to have a positive modulatory effect,either directly or indirectly, on the signalling mediated by the TrkA,TrkB and TrkC receptors, optionally in combination with a modulatoryeffect, either directly or indirectly, on the signalling mediated byreceptor tyrosine kinases such as IGF1R and/or FGFR1 receptor.

The invention relates to the compounds of the invention andpharmaceutically acceptable salts thereof, as defined above, for use intherapy. Without being bound to theory regarding the mode of action ofthe compounds defined above, it is believed that the compounds can beused for treatment and/or prevention of the diseases mentioned herein.

In particular embodiments, the diseases that may be treated by compoundsof the invention include Alzheimer's disease, depression, Parkinson'sdisease, other Parkinsonian disorders and/or other tauopathies, Lewybody dementia, multiple sclerosis, Huntington's disease, mild cognitiveimpairment, brain injuries (including traumatic brain injuries), stroke,other dementia disorders, motomeurone diseases, Pick disease, spinalchord injury, hypoxic ischemia injury, cognitive dysfunction, coronaryartery disease, obesity, metabolic syndrome, diabetes,Charcot-Marie-Tooth disease, diabetic neuropathy, tissue regeneration,diabetes-induced osteoporosis, motor function, nerve injury, hearingloss (including genetic or acquired hearing loss), blindness, posterioreye diseases, anterior eye diseases, dry eye disease, neurotrophickeratitis, glaucoma, high intraocular pressure (IOP), retinitispigmentosa, post-traumatic stress disorders, WAGR syndrome, Prader-Willisyndrome, diseases of the olfactory tract, olfactory decline, olfactorydysfunction, anxiety, fragile X syndrome, congenital centralhypoventilation syndrome, obsessive-compulsive disorder, generalizedanxiety disorder, eating disorders, bipolar disorder, chronic fatiguesyndrome, neuromyelitis optica, Rett syndrome, Friedrich's ataxia andobstructive sleep apnea-hypopnea syndrome.

In particular embodiments, the diseases that may be treated by compoundsof the invention include Alzheimer's disease, depression, Parkinson'sdisease, other Parkinsonian disorders and/or other tauopathies, Lewybody dementia, multiple sclerosis, Huntington's disease, mild cognitiveimpairment, brain injuries (including traumatic brain injuries), stroke,other dementia disorders, motomeurone diseases, Pick disease, spinalchord injury, hypoxic ischemia injury, cognitive dysfunction, coronaryartery disease, obesity, metabolic syndrome, diabetes,Charcot-Marie-Tooth disease, diabetic neuropathy, tissue regeneration,motor function, nerve injury, hearing loss, blindness, posterior eyediseases, dry eye disease, neurotrophic keratitis, glaucoma, highintraocular pressure (IOP), retinitis pigmentosa, post-traumatic stressdisorders, WAGR syndrome, diseases of the olfactory tract, olfactorydecline, olfactory dysfunction, anxiety, fragile X syndrome, congenitalcentral hypoventilation syndrome, obsessive-compulsive disorder,generalized anxiety disorder, eating disorders, bipolar disorder,chronic fatigue syndrome, neuromyelitis optica, Rett syndrome,Friedrich's ataxia and obstructive sleep apnea-hypopnea syndrome.

As used herein, the phrase “other Parkinsonian disorders” may beunderstood to refer to disorders that have symptoms similar toParkinson's disease, such as bradykinesia, tremors and posturalinstability. Examples of such disorders include progressive supranuclearpalsy (PSP), multiple system atrophy (MSA), and corticobasaldegeneration (CBD).

The phrase “other tauopathies” may be understood to refer toneurodegenerative diseases other than Alzheimer's disease that areassociated with the pathological misfolding of tau protein in the brain.Examples of such disorders include primary age-related tauopathy,progressive supranuclear palsy, Pick's disease, corticobasaldegeneration and post-encephalitic parkinsonism. The skilled person willunderstand that certain disorders such as progressive supranuclear palsymay be described as both a Parkinsonian disorder and a tauopathy.

The phrase “other dementia disorders” may be understood to includevascular dementia, mixed vascular dementia, incident dementia,post-operative dementia, presenile dementia, dementia associated withParkinson's disease and dementia due to HIV infection. Progressivesupranuclear palsy and corticobasal degeneration may also be classed asdementia disorders.

Motomeurone diseases include amyotrophic lateral sclerosis (ALS),hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS),progressive muscular atrophy (PMA), progressive bulbar palsy (PBP) andpseudobulbar palsy.

Cognitive dysfunction may be understood to refer to reduced cognitiveabilities in a patient including reduced ability in learning, memoryloss, perception, and problem solving. Cognitive dysfunction isassociated with a range of conditions, such as Alzheimer's disease,Parkinson's disease, progressive supranuclear palsy, corticobasaldegeneration and schizophrenia. Accordingly, in particular embodiments,the compounds of the invention may be used in the treatment of cognitivedysfunction in Alzheimer's disease, Parkinson's disease, progressivesupranuclear palsy, corticobasal degeneration or schizophrenia.Cognitive dysfunction also includes post-operative cognitive dysfunctionand impaired cognition associated with preterm delivery.

Similarly, in other particular embodiments, the compounds of theinvention may be used in improving cognition in a patient withAlzheimer's disease, Parkinson's disease, progressive supranuclearpalsy, corticobasal degeneration or schizophrenia. As used herein, thephrase “improving cognition” may be understood to indicate enhancing apatient's learning, memory, perception, and/or problem-solving ability.Improving cognition may also refer to slowing or arresting the rate ofdecline in cognition in a patient suffering from cognitive dysfunction(e.g. associated with the disorders listed above).

Cognitive function may be assessed using standard tests known to theperson skilled in the art. Examples of such tests include theAlzheimer's Disease Assessment Scale-Cognitive subscale test (ADAS-COG)the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating(CDR) the Clinical Dementia Rating-Sum of Boxes (CDR-SB), theAlzheimer's Disease Cooperative Study-Preclinical Alzheimer CognitiveComposite (ADCS-PACC) and the Repeatable Battery for the Assessment ofNeuropsychological Status (RBANS) test.

As used herein, “eating disorders” may be understood to includehyperphagia, anorexia nervosa, restricting anorexia nervosa and bulimianervosa.

In accordance with a further aspect of the invention, there is providedthe compounds of the invention, or a pharmaceutically acceptable saltthereof, for use in treatment and/or prevention of one or more diseaseselected from the group comprising or containing Alzheimer's disease,Lewy body dementia, frontotemporal dementia, HIV dementia, Huntington'sdisease, amyotrophic lateral sclerosis and other motor neuron diseases,Rett syndrome, epilepsy, Parkinson's disease and other parkinsoniandisorders, disorders in which enhancement of nerve regeneration isbeneficial, such as demyelinating diseases including multiple sclerosis,spinal cord injury, stroke, hypoxia, ischemia, brain injury includingtraumatic brain injury, mild cognitive impairment, dementia disorders(including dementia of mixed vascular and degenerative origin, preseniledementia, senile dementia and dementia associated with Parkinson'sdisease, progressive supranuclear palsy or corticobasal degeneration)and cognitive dysfunction in schizophrenia, obesity, diabetes andmetabolic syndrome, diabetic neuropathy including Charcot Marie Toothand its variants, nerve transplantation and its complications, diabetesinduced osteoporosis, motor neuron disease, peripheral nerve injury,genetic or acquired or traumatic hearing loss, blindness and posterioreye diseases, anterior eye diseases, depression, obesity, metabolicsyndrome, pain, depression, schizophrenia and anxiety.

In accordance with a further aspect of the invention, there is providedthe compounds of the invention, or a pharmaceutically acceptable saltthereof, for use in treatment and/or prevention of one or more diseaseselected from the group comprising or containing Alzheimer's disease,Lewy body dementia, frontotemporal dementia, HIV dementia, Huntington'sdisease, amyotrophic lateral sclerosis and other motor neuron diseases,Rett syndrome, epilepsy, Parkinson's disease and other parkinsoniandisorders, disorders in which enhancement of nerve regeneration isbeneficial, such as demyelinating diseases including multiple sclerosis,spinal cord injury, stroke, hypoxia, ischemia, brain injury includingtraumatic brain injury, mild cognitive impairment, dementia disorders(including dementia of mixed vascular and degenerative origin, preseniledementia, senile dementia and dementia associated with Parkinson'sdisease, progressive supranuclear palsy or corticobasal degeneration)and cognitive dysfunction in schizophrenia, obesity, diabetes andmetabolic syndrome, diabetic neuropathy including Charcot Marie Toothand its variants, nerve transplantation and its complications, motorneuron disease, peripheral nerve injury, genetic or acquired ortraumatic hearing loss, blindness and posterior eye diseases,depression, obesity, metabolic syndrome, pain, depression, schizophreniaand anxiety.

In more particular embodiments, the disease characterised by impairedsignalling of neurotrophins and/or other trophic factors is selectedfrom the group consisting of Alzheimer's disease, Parkinson's disease,other Parkinsonian diseases, other tauopathies, Lewy body dementia,motorneuron disease, Pick disease, obesity, metabolic syndrome, diabetesand Rett syndrome. The treatment of this group of disorders may beparticularly effective in patients having the Val66Met mutation in theBDNF gene.

In yet more particular embodiments, the disease characterised byimpaired signalling of neurotrophins and/or other trophic factors isselected from the group consisting of Alzheimer's disease, Parkinson'sdisease, Cognitive dysfunction, depression and Rett Syndrome.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use intreatment and/or prevention of Alzheimer's disease, Lewy body dementia,frontotemporal dementia, HIV dementia, Huntington's disease, amyotrophiclateral sclerosis and other motor neuron diseases, Rett syndrome,epilepsy, Parkinson's disease and/or other Parkinsonian disorders.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use intreatment and/or prevention of Alzheimer's disease, Parkinson's disease,Cognitive dysfunction in Schizophrenia, Rett's Syndrome and/ordepression.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use intreatment and/or prevention of Alzheimer's disease.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use intreatment and/or prevention of depression.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use intreatment and/or prevention of a disease where enhancement of nerveregeneration is beneficial, such as demyelinating diseases.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use intreatment and/or prevention of multiple sclerosis.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use intreatment and/or prevention of Rett syndrome.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use intreatment and/or prevention spinal cord injury, stroke, hypoxia,ischemia and/or brain injury including traumatic brain injury.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use in thetreatment and/or prevention of mild cognitive impairment, dementiadisorders (including dementia of mixed vascular and degenerative origin,presenile dementia, senile dementia and dementia associated withParkinson's disease, progressive supranuclear palsy, corticobasaldegeneration, post-operative dementia) and/or cognitive dysfunction inschizophrenia.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use in thetreatment and/or prevention of atherosclerosis, obesity, diabetes andmetabolic syndrome, diabetic neuropathy including Charcot Marie Toothand its variants, nerve transplantation and its complications, diabetesinduced osteoporosis, motor neuron disease, peripheral nerve injury,genetic or acquired or traumatic hearing loss, blindness and posterioreye diseases, depression, obesity, metabolic syndrome, WAGR syndrome,Prader-Willi syndrome and/or pain.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use in thetreatment and/or prevention of atherosclerosis, obesity, diabetes andmetabolic syndrome, diabetic neuropathy including Charcot Marie Toothand its variants, nerve transplantation and its complications, motorneuron disease, peripheral nerve injury, genetic or acquired ortraumatic hearing loss, blindness and posterior eye diseases,depression, obesity, metabolic syndrome and/or pain.

A further embodiment of the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, for use in thetreatment and/or prevention of depression, schizophrenia and/or anxiety.

A further embodiment of the invention relates to a compound of theinvention for use in the treatment and/or prevention of a diseaseselected from the group consisting of Alzheimer's disease, Parkinson'sdisease, another Parkinsonian disease, another tauopathy, Lewy bodydementia, motorneuron disease, Pick disease, obesity, metabolicsyndrome, diabetes and Rett syndrome.

A further embodiment of the invention relates to a compound of theinvention for use in the treatment and/or prevention of a diseaseselected from the group consisting of Alzheimer's disease, Parkinson'sdisease, another Parkinsonian disease, another tauopathy, Lewy bodydementia, motorneuron disease, Pick disease, obesity, metabolicsyndrome, diabetes and Rett syndrome, posterior eye diseases andcognitive dysfunction.

Another embodiment relates to a use of a compound of the invention, or apharmaceutically acceptable salt thereof, for the treatment and/orprevention of a disease in which modulators of neurotrophin receptors,such as TrkA, TrkB, TrkC and/or their signalling and receptor tyrosinekinases, such as FGFR1 and IGF1R and/or their signalling are beneficial,such as for the treatment and/or prevention of both non-neurological andneurological diseases, including one or more of the conditions mentionedhereinbefore.

The invention further relates to the use of a compound of the inventionin a method of treating, preventing or reducing the risk of a disease inwhich modulators of neurotrophin receptors, such as TrkA, TrkB, TrkCand/or their signalling and receptor tyrosine kinases, such as FGFR1 andIGF1R and/or their signalling, are beneficial, such as in the treatmentand/or prevention of both non-neurological and neurological diseases.

One embodiment relates to the use of a compound of the invention (forexample in the manufacture of a pharmaceutical medicament) for use in amethod of treating, preventing or reducing the risk of, one or moredisease mentioned hereinbefore, which comprises administering to amammal, such as a human, in need thereof, a therapeutically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt thereof.

Another embodiment relates to such a use of a compound of the inventionin a method of treating, preventing or reducing the risk of Alzheimer'sdisease, Lewy body dementia, frontotemporal dementia, HIV dementia,Huntington's disease, amyotrophic lateral sclerosis and other motorneuron diseases, Rett syndrome, epilepsy, Parkinson's disease and/orother parkinsonian disorders.

A further embodiment relates to such a use of a compound of theinvention in a method of treating, preventing or reducing the risk ofAlzheimer's disease, Parkinson's disease, Cognitive dysfunction inSchizophrenia, Rett's Syndrome and/or Depression.

A further embodiment relates to such a use of a compound of theinvention in a method of treating, preventing or reducing the risk of adisease where enhancement of nerve regeneration is beneficial such asdemyelinating diseases, such as multiple sclerosis.

A further embodiment relates to such a use of a compound of theinvention in a method of treating, preventing or reducing the risk ofspinal cord injury, stroke, hypoxia, ischemia and/or brain injuryincluding traumatic brain injury.

Another embodiment relates to such a use of a compound of the inventionin a method of treating, preventing or reducing the risk of mildcognitive impairment, dementia disorders (including dementia of mixedvascular and degenerative origin, presenile dementia, senile dementiaand dementia associated with Parkinson's disease, progressivesupranuclear palsy or corticobasal degeneration) and/or cognitivedysfunction in schizophrenia.

A further embodiment relates to such a use of a compound of theinvention in a method of treating, obesity, diabetes and metabolicsyndrome, diabetic neuropathy including Charcot Mae Tooth and itsvariants, nerve transplantation and its complications, diabetes inducedosteoporosis, motor neuron disease, peripheral nerve injury, genetic oracquired or traumatic hearing loss, blindness and posterior eyediseases, depression, obesity, metabolic syndrome and/or pain.

A further embodiment relates to such a use of a compound of theinvention in a method of treating, obesity, diabetes and metabolicsyndrome, diabetic neuropathy including Charcot Marie Tooth and itsvariants, nerve transplantation and its complications, motor neurondisease, peripheral nerve injury, genetic or acquired or traumatichearing loss, blindness and posterior eye diseases, depression, obesity,metabolic syndrome and/or pain.

Yet another embodiment relates to such a use of a compound of theinvention in a method of treating, preventing or reducing the risk ofdepression, schizophrenia and/or anxiety.

Pharmaceutical Compositions

As described herein, compounds of the invention are useful aspharmaceuticals. Such compounds may be administered alone or may beadministered by way of known pharmaceutical compositions/formulations.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising a compound of the invention, as defined herein,or a pharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable excipient, such as apharmaceutically-acceptable adjuvant diluent or carrier.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising a compound of the invention, or apharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable excipient, such as apharmaceutically-acceptable adjuvant, diluent or carrier, for use in thetreatment of a disease characterised by impaired signalling ofneurotrophins and/or other trophic factors (including the variousdiseases and disorders listed herein), optionally in a patient with theVal66Met mutation in the BDNF gene.

As used herein, the term pharmaceutically-acceptable excipients includesreferences to vehicles, adjuvants, carriers, diluents, pH adjusting andbuffering agents, tonicity adjusting agents, stabilizers, wetting agentsand the like. In particular, such excipients may include adjuvants,diluents or carriers.

The skilled person will understand that compounds of the invention mayact systemically and/or locally (i.e. at a particular site), and maytherefore be administered accordingly using suitable techniques known tothose skilled in the art.

The skilled person will understand that compounds and compositions asdescribed herein will normally be administered orally, intravenously,subcutaneously, buccally, rectally, dermally, nasally, tracheally,bronchially, sublingually, intranasally, topically (including topicaladministration to the eyes), by any other parenteral route or viainhalation, in a pharmaceutically acceptable dosage form.

Conventional procedures for the selection and preparation of suitablepharmaceutical formulations are described in, for example,“Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton,Churchill Livingstone, 1988. For preparing pharmaceutical compositionsfrom the compounds of the invention, inert, pharmaceutically acceptablecarriers can be either solid or liquid. Solid form preparations includepowders, tablets, dispersible granules, capsules, cachets, andsuppositories.

Pharmaceutical compositions as described herein will includeformulations in the form of tablets, capsules or elixirs for oraladministration, suppositories for rectal administration, sterilesolutions or suspensions for parenteral or intramuscular administration,and the like. Alternatively, particularly where such compounds of theinvention act locally, pharmaceutical compositions may be formulated fortopical administration. In particular, compounds may be formulated forlocal delivery to the CNS, for example in the form of artificialcerebrospinal fluid (CSF).

Thus, in particular embodiments, the pharmaceutical composition isprovided in a pharmaceutically acceptable dosage form, including tabletsor capsules, liquid forms to be taken orally or by injection,suppositories, creams, gels, foams, inhalants (e.g. to be appliedintranasally), or forms suitable for topical administration. For theavoidance of doubt, in such embodiments, compounds of the invention maybe present as a solid (e.g. a solid dispersion), liquid (e.g. insolution) or in other forms, such as in the form of micelles.

Thus, compounds, of the present invention, and compositions comprisingthe same, may be administered orally, parenteral, buccal, vaginal,rectal, inhalation, insufflation, sublingually, intramuscularly,subcutaneously, topically (including topical administration to theeyes), intranasally, intraperitoneally, intrathoracically,intravenously, epidurally, intrathecally, intracerebroventriculary andby injection into the joints.

Depending on the mode of administration, pharmaceutical compositionswill preferably comprise from 0.05 to 99% wt (percent by weight), morepreferably from 0.05 to 80% wt, still more preferably from 0.10 to 70%wt, and even more preferably from 0.10 to 50% wt, of a compounds of theinvention (calculated as a non-salt form), all percentages by weightbeing based on total composition.

Depending on e.g. potency and physical characteristics of the compoundof the invention (i.e. active ingredient), pharmaceutical formulationsthat may be mentioned include those in which the active ingredient ispresent in an amount that is at least 1% (or at least 10%, at least 30%or at least 50%) by weight. That is, the ratio of active ingredient tothe other components (i.e. the addition of adjuvant, diluent andcarrier) of the pharmaceutical composition is at least 1:99 (or at least10:90, at least 30:70 or at least 50:50) by weight.

The quantity of the compound to be administered will vary for thepatient being treated and will vary from about 100 ng/kg of body weightto 100 mg/kg of body weight per day. For instance, dosages can bereadily ascertained by those skilled in the art from this disclosure andthe knowledge in the art. Thus, the skilled artisan can readilydetermine the amount of compound and optional additives, vehicles,and/or carrier in compositions and to be administered in uses or methodsof the invention.

More, particularly, the skilled person will understand that compounds ofthe invention may be administered (for example, as formulations asdescribed hereinbefore) at varying doses, with suitable doses beingreadily determined by one of skill in the art. Oral, pulmonary andtopical dosages (and subcutaneous dosages, although these dosages may berelatively lower) may range from between about 0.01 μg/kg of body weightper day (μg/kg/day) to about 200 μg/kg/day, preferably about 0.01 toabout 10 μg/kg/day, and more preferably about 0.1 to about 5.0μg/kg/day. For example, when administered orally, treatment with suchcompounds may comprise administration of a formulations typicallycontaining between about 0.01 μg to about 2000 mg, for example betweenabout 0.1 μg to about 500 mg, or between 1 μg to about 100 mg (e.g.about 20 μg to about 80 mg), of the active ingredient(s). Whenadministered intravenously, the most preferred doses will range fromabout 0.001 to about 10 μg/kg/hour during constant rate infusion.Advantageously, treatment may comprise administration of such compoundsand compositions in a single daily dose, or the total daily dosage maybe administered in divided doses of two, three or four times daily (e.g.twice daily with reference to the doses described herein, such as a doseof 25 mg, 50 mg, 100 mg or 200 mg twice daily).

For the avoidance of doubt, the skilled person (e.g. the physician) willbe able to determine the actual dosage which will be most suitable foran individual patient, which is likely to vary with the route ofadministration, the type of formulation, the type and severity of thecondition that is to be treated, other medication the patient may betaking, as well as the species, age, weight, size, sex, diet, renalfunction, hepatic function, general physical condition, genetic factorsand response of the particular patient to be treated. Although theabove-mentioned dosages are exemplary of the average case, there can, ofcourse, be individual instances where higher or lower dosage ranges aremerited, and such doses are within the scope of the invention.

Thus, in a further aspect of the invention, there is provided a use of apharmaceutical composition, as defined above, in therapy, or for thetreatment and/or prevention of a disease in which modulators ofneurotrophin receptors, such as TrkA, TrkB, TrkC and/or their signallingand receptor tyrosine kinases, such as FGFR1 and IGF1R and/or theirsignalling, are beneficial, such as in the treatment and/or preventionof both non-neurological and neurological diseases mentionedhereinbefore.

Combinations and Kits-of-Parts

The treatment and/or prevention of diseases of the nervous system andrelated pathology defined herein may be applied as a sole therapy or mayinvolve, in addition to the compound of the invention, conjointtreatment with conventional therapy of value in treating one or moredisease conditions referred to herein. Such conventional therapy mayinclude one or more agents such as acetyl cholinesterase inhibitors,anti-inflammatory agents, cognitive and/or memory enhancing agents,atypical antipsychotic agents, dopamine agonists and/or L-DOPA.

Such conjoint treatment and/or prevention may be achieved by way of thesimultaneous, sequential or separate dosing of the individual compoundsof the invention or additional agents of the treatment and/orprevention. Such combination products employ the compounds, orpharmaceutically acceptable salts thereof, of the invention.

Accordingly, the skilled person will understand that treatment withcompounds of the invention may further comprise (i.e. be combined with)further treatment(s) or preventative methods for the same condition. Inparticular, treatment with compounds of the invention may be combinedwith means for the treatment of diseases characterised by impairedsignalling of neurotrophins and/or other trophic factors (such asAlzheimer's disease, Parkinson's disease, cognitive dysfunction anddepression as described herein, e.g. Alzheimer's disease) such astreatment with one or more other therapeutic agent that is useful in thein the treatment the various diseases characterised by impairedsignalling of neurotrophins and/or other trophic factors describedherein, and/or one or more physical method used in the treatment (suchas treatment through surgery), as known to those skilled in the art.

As described herein, compounds of the invention may also be combinedwith one or more other (i.e. different) therapeutic agents (i.e. agentsthat are not compounds of the invention) that are useful in thetreatment and/or prevention of diseases characterised by impairedsignalling of neurotrophins and/or other trophic factors. Suchcombination products that provide for the administration of a compoundof the invention in conjunction with one or more other therapeutic agentmay be presented either as separate formulations, wherein at least oneof those formulations comprises a compound of the invention, and atleast one comprises the other therapeutic agent, or may be presented(i.e. formulated) as a combined preparation (i.e. presented as a singleformulation including a compound of the invention and the one or moreother therapeutic agent).

Thus, according to a further aspect of the invention, there is provideda combination product comprising:

-   (I) a compound of the invention as hereinbefore defined, or a    pharmaceutically acceptable salt thereof; and-   (II) one or more other therapeutic agent that is useful in the    treatment or prevention of a disease characterised by impaired    signalling of neurotrophins and/or other trophic factors,

wherein each of components (I) and (II) is formulated in admixture,optionally with a pharmaceutically-acceptable excipient, such as apharmaceutically-acceptable adjuvant diluent or carrier.

Accordingly to a further aspect of the invention there is provided apharmaceutical composition comprising a compound of the invention ashereinbefore defined, or a pharmaceutically acceptable salt thereof, oneor more other therapeutic agent that is useful in the treatment orprevention of a disease characterised by impaired signalling ofneurotrophins and/or other trophic factors, formulated together inadmixture, optionally with a pharmaceutically-acceptable excipient, suchas a pharmaceutically-acceptable adjuvant diluent or carrier.

According to a further aspect of the invention, there is provided akit-of-parts comprising:

(a) a pharmaceutical composition comprising a compound of the inventionas hereinbefore defined, or a pharmaceutically acceptable salt thereof,formulated in admixture, optionally with a pharmaceutically-acceptableexcipient, such as a pharmaceutically-acceptable adjuvant diluent orcarrier; and

(b) a pharmaceutical composition comprising one or more othertherapeutic agent that is useful in the treatment or prevention of adisease characterised by impaired signalling of neurotrophins and/orother trophic factors, formulated in admixture, optionally with apharmaceutically-acceptable excipient, such as apharmaceutically-acceptable adjuvant diluent or carrier,

which components (a) and (b) are each provided in a form that issuitable for administration in conjunction with the other.

With respect to the kits-of-parts as described herein, by“administration in conjunction with” (and similarly “administered inconjunction with”) we include that respective formulations areadministered, sequentially, separately or simultaneously, as part of amedical intervention directed towards treatment of the relevantcondition.

Thus, in relation to the present invention, the term “administration inconjunction with” (and similarly “administered in conjunction with”)includes that the two active ingredients are administered (optionallyrepeatedly) either together, or sufficiently closely in time, to enablea beneficial effect for the patient, that is greater, over the course ofthe treatment and/or prevention of the relevant condition, than ifeither agent is administered (optionally repeatedly) alone, in theabsence of the other component, over the same course of treatment and/orprevention. Determination of whether a combination provides a greaterbeneficial effect in respect of, and over the course of, treatment orprevention of a particular condition will depend upon the condition tobe treated or prevented, but may be achieved routinely by the skilledperson.

Further, in the context of the present invention, the term “inconjunction with” includes that one or other of the two formulations maybe administered (optionally repeatedly) prior to, after, and/or at thesame time as, administration of the other component. When used in thiscontext, the terms “administered simultaneously” and “administered atthe same time as” includes instances where the individual doses of thecompound of the invention and the additional compound for the treatmentof a disease characterised by impaired signalling of neurotrophinsand/or other trophic factors, or pharmaceutically acceptable saltsthereof, are administered within 48 hours (e.g. within 24 hours, 12hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20minutes or 10 minutes) of each other.

Other therapeutic agents useful in the treatment or prevention ofdiseases characterised by impaired signalling of neurotrophins and/orother trophic factors will be well-known to those skilled in the art.For example, such other therapeutic agents may include: acetylcholinesterase inhibitors, anti-inflammatory agents, cognitive enhancingagents, memory enhancing agents, and atypical antipsychotic agents,anti-depressive agents, anti-Alzheimer agents, beta-secretaseinhibitors, gamma-secretase modulators, agents modifying tau function,amyloid-beta production inhibitors, antibodies directed at amyloid-beta,antibodies directed at tau, antibodies directed at alpha-synuclein,anti-Parkinson agents, anti-diabetic agents, anti-multiple sclerosisagents, anti-obesity agents, agents used for treatment of auditorydysfunction, agents used for treatment of ocular disease, agents usedfor the treatment of olfactory dysfunction, agents used for thetreatment of gustatory dysfunction, anti-huntington agents, anti-Rettsyndrome agents, anti-stroke agents. Particular therapeutic agents thatmay be mentioned include acetyl cholinesterase inhibitors,anti-Alzheimer agents, anti-Parkinson agents, cognitive enhancingagents, antibodies directed at amyloid-beta, antibodies directed at tau,antibodies directed at alpha-synuclein, beta-secretase inhibitors,gamma-secretase modulators, NGF, BDNF, NT-3; NT-4/5, IGF-1, FGF, GDNF,CTNF and/or HGF.

Preparation of Compositions

Pharmaceutical compositions/formulations, combination products and kitsas described herein may be prepared in accordance with standard and/oraccepted pharmaceutical practice.

Thus, in a further aspect of the invention there is provided a processfor the preparation of a pharmaceutical composition/formulation, ashereinbefore defined, which process comprises bringing into associationa compound of the invention, as hereinbefore defined, with one or morepharmaceutically-acceptable excipient.

In further aspects of the invention, there is provided a process for thepreparation of a combination product or kit-of-parts as hereinbeforedefined, which process comprises bringing into association a compound ofthe invention, as hereinbefore defined, with the other therapeutic agentthat is useful in the treatment of the relevant disease or disorder, andat least one pharmaceutically-acceptable excipient.

As used herein, references to bringing into association will mean thatthe two components are rendered suitable for administration inconjunction with each other.

Thus, in relation to the process for the preparation of a kit-of-partsas hereinbefore defined, by bringing the two components “intoassociation with” each other, we include that the two components of thekit-of-parts may be:

(i) provided as separate formulations (i.e. independently of oneanother), which are subsequently brought together for use in conjunctionwith each other in combination therapy; or

(ii) packaged and presented together as separate components of a“combination pack” for use in conjunction with each other in combinationtherapy.

Preparation of Compounds of the Invention

Compounds of the invention as described herein may be prepared either asa free base or as a pharmaceutically acceptable salt in accordance withtechniques that are well known to those skilled in the art, such asthose described in the examples provided hereinafter.

According to a further aspect of the invention there is provided aprocess for the preparation of a compound of the invention, whichcomprises the step of reaction of a compound of formula II,

wherein R¹, R², n, X, Q, L, m, R³ and p are as hereinbefore defined,with a suitable isocyanate (e.g. methoxycarbonyl isocyante,chlorocarbonyl isocyanate or, preferably, ethoxycarbonyl isocyanate).

This reaction may be performed for example:

-   -   (a) in a sealed microwave vial in a suitable solvent (such as        toluene or bromobenzene), at a suitable reaction temperature        (e.g. between room temperature and reflux temperature); or    -   (b) by first treating the compound of formula II with a suitable        base, such as sodium hydride, at a suitable reaction temperature        (e.g. between 0° C. and room temperature) for between about 1        and about 60 minutes in a suitable solvent, such as DMF,        followed by the addition of the ethoxycarbonyl isocyanate at        approximately the same, with stirring, for a suitable time, such        as between about 1 and about 60 minutes.

Compounds of formula II may be obtained by reacting a compound offormula III,

wherein R², n, X, Q, L, m, R³ and p are as hereinbefore defined, witheither:

-   -   (a) a compound of formula IV,        R¹—N═C═O  (IV)        -   wherein R¹ is as hereinbefore defined; or    -   (b) a compound of formula V,        R¹—N(H)C(O)Cl  (V)        -   wherein R¹ is as hereinbefore defined, for example (in both            cases) in the presence of a suitable base, such as TEA, in a            suitable solvent, such as DCM, THF or, pyridine, at a            suitable reaction temperature (for example between room            temperature and reflux temperature).

Compounds of formula II may alternatively be obtained by reacting acompound of formula VI,

wherein R², n, X, Q, L, m, R³ and p are as hereinbefore defined, with anamine of formula VII,R¹—NH₂  (VII)

wherein R¹ is as hereinbefore defined, for example in the presence of asuitable base, such as TEA, in a suitable solvent, such as THF, and at asuitable reaction temperature (e.g. between room temperature and refluxtemperature).

Compounds of formula II may alternatively be prepared by reacting acompound of formula III as hereinbefore defined with triphosgene orphosgene in the presence of a suitable base, such as NaHCO₃ or TEA, in asuitable solvent, such as DCM, and at a suitable reaction temperature(e.g. between 0° C. and room temperature). After a suitable period oftime, such as between about 1 and about 6 hours, a compound of formulaVII may be added, together with an additional amount of a suitable (e.g.the above-mentioned) base, which reaction mixture is then allowed toreact at a suitable temperature, such as room temperature, for asuitable period of time, such as between about 1 and about 24 hours.Alternatively, the sequence of this reaction may be altered by firstreacting a compound of formula IV with triphosgene or phosgene, followedby the addition of the compound of formula VII, under substantially thesame reaction conditions as described above.

Compounds of formula III may be obtained by reducing a compound offormula VIII,

wherein R², n, X, Q, L, m, R³ and p are as hereinbefore defined, in thepresence of a suitable reducing agent such as SnCl₂.2H₂O, for example inthe presence of HCl, or using Pd/C in the presence of H₂(g). Thisreaction may be performed in a suitable solvent, such as ethanol, and ata suitable temperature (for example between room temperature and refluxtemperature).

In a further embodiment of the invention, there is provided a processfor the preparation of a compound of the invention, which comprises thestep of reacting a compound of formula IX

wherein R¹, R², n, X, Q, L, m, R³ and p are as hereinbefore defined,with a compound of formula X,

wherein LG¹ and LG² represent suitable leaving groups independentlyselected from chloro, methoxy, ethoxy and 1-imidazolyl (particularcompounds of formula X that may be mentioned include diethylcarbonate),in the presence of a suitable solvent, such as ethanol and optionally asuitable base, such as sodium ethoxide or methoxide.

Compounds of formula IX may be obtained by reacting a compound offormula (X),

wherein R², n, X, Q, L, m, R³ and p are as hereinbefore defined, with acompound of formula (XII),

wherein R¹ is as defined herein above, in the presence of a suitablesolvent, such as dichloromethane or tetrahydrofuran and, optionally asuitable base, such as triethylamine.

Compounds of formula XI may be obtained by reacting a compound offormula III with triphosgene or phosgene.

In a further embodiment of the invention, there is provided a processfor the preparation of a compound of the invention, which comprises thestep of reacting a compound of formula XIII,

wherein R¹, R², n, X, Q, L, m, R³ and p are as hereinbefore defined,with a compound of formula X, as defined herein, such as diethylcarbonate, in the presence of a suitable solvent, such as ethanol and,optionally, a suitable base, such as sodium ethoxide.

Compounds of formula XIII may be obtained by reacting a compound offormula II with phosgene or triphosgene in the presence of a suitablesolvent, and optionally a suitable base, followed by the addition ofammonia to the reaction mixture.

In a further embodiment of the invention, there is provided a processfor the preparation of a compound of the invention, which comprises thestep of reacting a compound of formula XIV,

wherein R¹, R², n, X, Q, L, m, R³ and p are as hereinbefore defined,particularly wherein R¹ represents an aryl or heteroaryl group asdefined herein (more particularly wherein R¹ represents phenyl), in thepresence of an aqueous acid (such as HCl (e.g. 2M HCl)) and optionallyan organic co-solvent (e.g. 1,4-dioxane), and at a suitable temperature(for example at between room temperature and reflux temperature).

Compounds of formula XIV may be obtained by reacting a compound offormula XV,

wherein R², n, X, Q, L, m, R³ and p are as hereinbefore defined, with anexcess (e.g. 2 equivalents) of a compound of formula XVI,R¹—N═C═O  (XVI)

wherein R¹ is as hereinbefore defined, particularly wherein R¹represents an aryl or heteroaryl group as defined herein (moreparticularly wherein R¹ represents phenyl), in the presence of asuitable base (e.g. triethylamine) and a suitable solvent (e.g.acetonitrile), and at a suitable temperature (e.g., room temperature).

Compounds of formula XIV may be obtained by reacting a compound offormula III as defined herein, with dimethyl cyanocarbonimidodithioatein the presence of a suitable solvent (e.g. ethanol) at a suitabletemperature (e.g. reflux temperature) for a suitable period of time (forexample an extended period of time, such as more than 5 days (e.g. morethan 10 days).

Compounds of formulae IV, V, VI, VII, VIII, X, XII and XVI are eithercommercially available, are known in the literature, or may be obtainedeither by analogy with the processes described herein, or byconventional synthetic procedures, in accordance with standardtechniques, from available starting materials using appropriate reagentsand reaction conditions. In this respect, the skilled person may referto inter alia “Comprehensive Organic Synthesis” by B. M. Trost and I.Fleming, Pergamon Press, 1991. Further references that may be employedinclude “Heterocyclic Chemistry” by J. A. Joule, K. Mills and G. F.Smith, 3^(rd) edition, published by Chapman & Hall, “ComprehensiveHeterocyclic Chemistry II” by A. R. Katritzky, C. W. Rees and E. F. V.Scriven, Pergamon Press, 1996 and “Science of Synthesis”, Volumes 9-17(Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

The skilled person will understand that the substituents as definedherein, and substituents thereon, may be modified one or more times,after or during the processes described above for the preparation ofcompounds of the invention by way of methods that are well known tothose skilled in the art. Examples of such methods includesubstitutions, reductions, oxidations, dehydrogenations, alkylations,dealkylations, acylations, hydrolyses, esterifications, etherifications,halogenations and nitrations. The precursor groups can be changed to adifferent such group, or to the groups defined in formula I, at any timeduring the reaction sequence. The skilled person may also refer to“Comprehensive Organic Functional Group Transformations” by A. R.Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995 and/or“Comprehensive Organic Transformations” by R. C. Larock, Wiley-VCH,1999.

Compounds of the invention may be isolated from their reaction mixturesand, if necessary, purified using conventional techniques as known tothose skilled in the art. Thus, processes for preparation of compoundsof the invention as described herein may include, as a final step,isolation and optionally purification of the compound of the invention.

It will be appreciated by those skilled in the art that, in theprocesses described above and hereinafter, the functional groups ofintermediate compounds may need to be protected by protecting groups.The protection and deprotection of functional groups may take placebefore or after a reaction in the above-mentioned schemes.

Protecting groups may be applied and removed in accordance withtechniques that are well-known to those skilled in the art and asdescribed hereinafter. For example, protected compounds/intermediatesdescribed herein may be converted chemically to unprotected compoundsusing standard deprotection techniques. The type of chemistry involvedwill dictate the need, and type, of protecting groups as well as thesequence for accomplishing the synthesis. The use of protecting groupsis fully described in “Protective Groups in Organic Synthesis”, 3rdedition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1999), thecontents of which are incorporated herein by reference.

When used herein in relation to a specific value (such as an amount),the term “about” (or similar terms, such as “approximately”) will beunderstood as indicating that such values may vary by up to 10%(particularly, up to 5%, such as up to 1%) of the value defined. It iscontemplated that, at each instance, such terms may be replaced with thenotation “±10%”, or the like (or by indicating a variance of a specificamount calculated based on the relevant value). It is also contemplatedthat, at each instance, such terms may be deleted.

Compounds of the invention may have the advantage that they may be moreefficacious than, be less toxic than, be longer acting than, be morepotent than, produce fewer side effects than, be more easily absorbedthan, and/or have a better pharmacokinetic profile (e.g. higher oralbioavailability and/or lower clearance) than, and/or have other usefulpharmacological, physical, or chemical properties over, compounds knownin the prior art, whether for use in the above-stated indications orotherwise. In particular, compounds of the invention may have theadvantage that they are more efficacious and/or exhibit advantageousproperties in vivo.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows the results of the passive avoidance task described in thebiological examples. The graph demonstrates that administering thecompound of Example 5 to mice treated with scopolamine improvescognitive function, as illustrated by the increased retention latencywithin the bright area.

EXAMPLES

The present invention will be further described by reference to thefollowing examples, which are not intended to limit the scope of theinvention.

Experimental Procedures

Starting materials and intermediates used in the synthesis of compoundsdescribed herein are commercially available or can be prepared by themethods described herein or by methods known in the art.

Experiments were generally carried out under inert atmosphere (nitrogenor argon), particularly in cases where oxygen- or moisture-sensitivereagents or intermediates were used.

Mass spectrometry data are reported from liquid chromatography-massspectrometry (LC-MS) using electrospray ionization. Chemical shifts forNMR data are expressed in parts per million (ppm, δ) referenced toresidual peaks from the deuterated solvent used.

For syntheses referencing general procedures, reaction conditions (suchas length of reaction or temperature) may vary. In general, reactionswere followed by thin layer chromatography or LC-MS, and subjected towork-up when appropriate. Purifications may vary between experiments: ingeneral, solvents and the solvent ratios used for eluents/gradients werechosen to provide an appropriate R and/or retention time.

General Methods:

All solvents were of analytical grade and commercially availableanhydrous solvents were routinely used for reactions. Starting materialsused were available from commercial sources or prepared according toliterature procedures, Room temperature refers to 20-25° C. Solventmixture compositions are given as volume percentages or volume ratios.

MW heating was performed in a standard MW reactor producing continuousirradiation at 2450 MHz. It is understood that MWs can be used for theheating of reaction mixtures.

Thin layer chromatography (TLC) was performed on Merck TLC-plates(Silica gel 60 F₂₅₄) and spots were UV visualized. TLC was generallyused to monitor reaction progression and solvents used were for example:ethyl acetate or acetonitrile or DCM with 1-10% of MeOH, ethyl acetatewith 0-95% hexane. Straight phase flash column chromatography (“flashchromatography”/“column chromatography”) was manually performed on MerckSilica gel 60 (0.040-0.063 mm) or basic aluminum oxide or neutralaluminum oxide, or automatically using ISCO Combiflash® Companion™system using RediSep™ normal-phase flash columns (“Combiflash”) usingthe solvent system indicated.

NMR spectra was recorded on a 400 MHz NMR spectrometer (Bruker 400 MHzAvance-Ill) fitted with a probe of suitable configuration. Spectra wererecorded at ambient temperature unless otherwise stated. Chemical fieldsare given in ppm down- and upfield from TMS (0.00 ppm). The followingreference signals were used in ¹H-NMR: TMS ∂ 0.00, or residual solventsignal of DMSO-d6 δ 2.49, CDCL3 δ 7.25 (unless otherwise indicated).Resonance multiplicities are denoted s, d, t, q, m, dd, tt, dt br andapp for singlet, doublet, triplet, quartet, doublet of doublet, tripletof triplet, doublet of triplet, multiplet, broad and apparent,respectively. In some cases only diagnostic signals are reported.

High pressure liquid chromatography (HPLC) was performed on a reversedphase (RP) column. A gradient was applied using for example mobile phaseA (5 mM Ammonium acetate+0.1% Formic acid in water) and B (0.1% Formicacid in Acetonitrile) or A (0.1% NH3 in water) and B (0.1% NH3 inacetonitrile) or A (10 mM Ammonium acetate in water) and B(Acetonitrile).

Reversed phase columns used were for example: BEH C18 (50*2.1 mm), 1.7μm; X-Bridge C18 (50*4.6 mm), 3.5 μm; X-Bridge/YMCC18 (150*4.6 mm), 5μm; BEH C18 (50*2.1 mm), 1.7 μm; X-Bridge C8 (250*19) mm, 5 μm. Theflowrate used was for example 0.55 ml/min or 1.00 ml/min

Mass spectrometry (MS) analysis were performed in positive and/ornegative ion mode using electrospray ionization (ESI+/−).

Preparative HPLC chromatography was run on a Waters e2695 SeparationModule with a PDA Detector. Column; X-BRIDGE C18, 150*4.6 mm, 5 μm orX-Bridge C18 (250*19 mm) 5 μm or GEMINI C18 (250*21.2 mm) 5 μm.

A gradient was applied using for example mobile phase A (0.1% NH₃ inwater) and B (0.1% NH3 in acetonitrile); A (0.1% TFA in water) and B(Acetonitrile); A (5 mM ammonium bicarbonate+0.05% ammonia in water) andB (Acetonitrile); A (5 mM ammonium bicarbonate) and B (acetonitrile) forLC-separation at a flow rate 1 ml/min.

High pressure liquid chromatography (HPLC) was performed on a straightphase column. A linear gradient or isocratic flow was applied using forexample phase A (Hexane) and B (XX)

Compounds have been named using CDD vault from Collaborative DrugDiscovery Inc. Burlingame Calif., USA or ChemDoodle 8.1.0 from iChemLabsLLC, USA or ACD/ChemSketch 2012 (14.01) from Advanced ChemistryDevelopment (ACD/labs) Ontario, Canada. In case of inconsistency betweena name of a compound and the structural formula of the same compound, itis the structural formula that is decisive for the molecular structureof the compound.

In the event that there is a discrepancy between nomenclature and anycompounds depicted graphically, then it is the latter that presides(unless contradicted by any experimental details that may be given orunless it is clear from the context).

Intermediate 1 1-(4-phenoxyphenyl)-3-phenylurea

Phenyl isocyanate (0.115 g, 0.00097 mol) was added to a solution of4-phenoxyaniline (commercially available, 0.150 g, 0.00081 mol) inpyridine under N₂ (g). The reaction mixture was heated to 90° C. for 1hour. The reaction mixture was diluted with water (50 ml) and extractedwith ethyl acetate (3×40 ml). The combined organic layers were washedwith brine (30 ml), dried over sodium sulfate and evaporated underreduced pressure to obtain crude product. The crude product was purifiedon silica gel (100-200 mesh) using 50% ethyl acetate in hexane as aneluent to obtain 0.200 g (81% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.93-7.04 (m, 5H) 7.09 (m, 1H) 7.28 (m,2H) 7.37 (m, 2H) 7.47 (m, 4H) 8.67 (m, 2H); MS (ES+) m/z 305 [M+H]⁺

Intermediate 2 1-(4-methoxyphenyl)-3-(4-phenoxyphenyl)urea

To a solution of phenyl (4-phenoxyphenyl)carbamate (commerciallyavailable, 0.300 g, 0.00091 mol) in THF (3.0 mL), TEA (0.273 g, 0.0019mol) and 4-Methoxy Aniline (0.145 g, 0.0011 mol) were added at 0° C.under N₂ (g). The reaction mixture was heated at 70° C. 16 h. Thereaction mixture was quenched with ice-water (30 ml) and extracted withEthyl Acetate (3×40 ml). The combined organic layers were washed withbrine (50 ml). The Organic layer was dried over sodium sulfate andevaporated under reduced pressure to obtain crude product. The crudeproduct was purified on column chromatography using 45% Ethyl acetate inHexane as a mobile phase and 60-120 silica as stationary phase to yield0.214 g (77% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 3.72 (s, 3H) 6.91-6.83 (m, 2H) 7.02-6.91 (m, 4H) 7.09 (app tt, 1H)7.42-7.30 (m, 4H) 7.50-7.43 (m, 2H) 8.45 (s, 1H) 8.59 (s, 1H); MS (ES+)m/z 335 [M+H]⁺

Intermediate 3 1-(3-cyanophenyl)-3-(4-phenoxyphenyl)urea

TEA (0.273 g, 0.0019 mol) was added dropwise to phenyl(4-phenoxyphenyl)carbamate (commercially available, 0.30 g, 0.00098 mol)followed by 3-amino-benzonitrile (0.139 g, 0.0011 mol) in THF (3.00 mL)under N₂ (g) at 0° C. The reaction mixture was stirred at 70° C. for 16h. The reaction mixture was quenched with ice-water (20 ml) and productwas extracted with Ethyl Acetate (3×20 ml). The combined organic layerswere washed with brine (20 ml), over sodium sulfate and evaporated underreduced pressure to obtain the crude product. The crude product waspurified on column chromatography using 30% ethyl acetate in hexane as amobile phase and 60-120 silica as stationary phase to yield 0.139 g (46%yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.92-7.05(m, 4H) 7.10 (app tt, 1H) 7.32-7.46 (m, 3H) 7.44-7.54 (m, 3H) 7.68 (appddd, 1H) 7.98 (app t, 1H) 8.86 (s, 1H) 9.01 (s, 1H).

Intermediate 4 1-(3-methoxyphenyl)-3-(4-phenoxyphenyl)urea

m-Anisidine (0.145 g, 0.00170 mol) and TEA (0.273 g, 0.00196 mol) wereadded to a solution of phenyl-(4-phenoxyphenyl)carbamate (commerciallyavailable, 0.300 g, 0.00098 mol) in THF (3.0 mL) under stirring at 0° C.under N2 (g). The reaction mixture was stirred at 70° C. for 16 h. Thereaction mixture was quenched with ice-water (50 ml) and extracted withethyl acetate (3×40 ml). The combined organic layers were washed withbrine (30 ml), dried over sodium sulfate and evaporated under reducedpressure to obtain crude product. The crude product was purified bycolumn chromatography using 55% ethyl acetate in hexane as a mobilephase and 60-120 silica as stationary phase to yield 0.200 g (66% yield)of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3H) 6.55(m, 1H) 6.81-7.03 (m, 5H) 7.09 (app tt, 1H) 7.13-7.22 (m, 2H) 7.32-7.42(m, 2H) 7.42-7.51 (m, 2H) 8.66 (app s, 2H); MS (ES+) m/z 335 [M+H]⁺

Intermediate 5 1-(3-methyl-4-phenoxyphenyl)-3-phenylurea

Phenyl isocyanate (6.53 g, 0.0548 mol) was added to a solution of3-methyl-4-phenoxyaniline (commercially available, 8.40 g, 0.0390 mol)and TEA (11.76 mL, 0.084 mol) in DCM at 0° C. The reaction mixture wasstirred at 25° C. for 16 h. The solid produced was filtered off and washwith n-pentane (20 ml) to yield 8.4 g (67% yield) of the title compound.This material was used in the next step without further purification. ¹HNMR (400 MHz, DMSO-d6) δ ppm 2.12 (s, 3H) 6.81-6.91 (m, 3H) 6.88-7.08(m, 3H) 7.24-7.38 (m, 4H) 7.40-7.50 (m, 3H) 8.64 (app d, 2H); MS (ES+)m/z 319 [M+H]⁺

Intermediate 6 4-(benzyloxy)aniline

In a 30 ml seal tube previously equipped with a magnetic stirrer andnitrogen balloon Potassium tert-butoxide (0.76 mg, 0.0068 mol) was addedportion wise to a solution of 4-aminophenol (0.50 g, 0.0045 mol) in DMF(5.0 mL) at 0° C. After stirring for 1 h, benzylbromde (0.860 g, 0.005mol) was added portion wise. The reaction mixture was allowed to come at25° C. than heated at 120° C. for 16 hours. The reaction mixture wasquenched with water (50 ml) and extracted with ethyl acetate (3×40 ml).The combine organic layers were washed with brine (30 ml), dried oversodium sulfate and evaporated under reduced pressure to obtain the crudeproduct. The crude product was purified on silica gel (60-120 mesh)using 30% ethyl acetate in hexane as an eluent to obtained 0.400 g (44%yield) of the pure title product.

MS (ES+) m/z 200 [M+H]⁺

Intermediate 7 1-[4-(benzyloxy)phenyl]-3-phenylurea

Phenylisocyanate (0.286 g, 0.0024 mol) was added to a solution of4-(benzyloxy)aniline (Intermediate 6, 0.400 g, 0.0020) and TEA (0.404ml, 0.0040 mol) in DCM (4.00 ml) at 0° C. The resulting reaction mixturewas allowed to come to 25° C. and stirred at 25° C. for 2 hrs. Thesolvent was evaporated under reduce pressure to obtain 0.450 g (71%yield) of the title compound. This material was used without furtherpurification in the next step. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 5.06 (s,2H) 6.95 (app dd, 3H) 7.22-7.33 (m, 3H) 7.34 (app dd, 3H) 7.41 (app dt,5H) 8.58 (s, 1H), 8.47 (s, 1H); MS (ES+) m/z 319 [M+H]⁺

Intermediate 8 1-[4-(4-chlorophenoxy)phenyl]-3-phenylurea

Phenyl isocyanate (0.140 g, 0.00110 mol) was added to a solution of4-(4-chlorophenoxy)aniline (commercially available, 0.200 g, 0.00091mol) and TEA (0.255 ml, 0.00180 mol) in DCM (4.00 mL) under stirring at0° C. The resulting reaction mixture was allowed to reach 25° C. andstirred for 16 h. The solid formed was filtered off and washed withn-pentane (3×15 ml) to yield 0.310 g of title compound. This solid wasused in the next step without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 6.99 (m, 5H) 7.28 (m, 3H), 7.36-7.54 (m, 5H), 8.66 (s,1H) 8.71 (s, 1H); MS (ES+) m/z 339 [M+H]⁺

Intermediate 9 4-(4-aminophenoxy)benzonitrile

Potassium tert-butoxide (1.02 g, 0.0091 mol) was added portion wise tothe solution of 4-aminophenol (0.500 g, 0.0015 mol) in DMF (5.00 mL) at0° C. under N₂ (g). After 1 hour, 4-bromobenzonitrile (0.830 g, 0.0045mol) was added portion wise and the reaction mixture was stirred at 120°C. for 16 hours. The reaction mixture was quenched with ice-water (50ml) and product was extracted with Ethyl Acetate (3×40 ml). The combinedorganic layer was washed with brine (30 ml). The organic layer was driedover sodium sulfate and evaporated under reduced pressure to obtaincrude product. The crude product was purified on column chromatographyusing 100% Ethyl acetate in hexane as a mobile phase and 60-120 silicato yield 0.350 g (36% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 5.12 (s, 2H) 6.57-6.65 (m, 2H) 6.79-6.86 (m, 2H)6.94-7.00 (m, 2H) 7.73-7.80 (m, 2H).

Intermediate 10 1-[4-(4-cyanophenoxy)phenyl]-3-phenylurea

Phenyl isocyanate was added to a solution of4-(4-aminophenoxy)benzonitrile (Intermediate 9, 0.150 g, 0.00071 mol)and TEA (0.100 ml, 0.00071 mol) in DCM (5.00 mL) at 0° C. The reactionmixture was stirred at 25° C. for 16 h. The solvent was evaporated andthe reaction mixture was quenched with water (25 ml) and was extractedwith Ethyl Acetate (3×30 ml). The combined organic layer was washed withbrine (30 ml). The organic layer was dried over sodium sulfate andevaporated under reduce pressure to obtain a crude product. The crudeproduct was purified on column chromatography using 40% ethyl acetate inhexane as a mobile phase and 60-120 silica as stationary phase to yield0.250 g of the title compound that was used in the next step withoutfurther purification. MS (ES+) m/z 330 [M+H]⁺

Intermediate 11 1-(48-methoxy-4-phenoxyphenyl)-3-phenylurea

2-methoxy-4-phenoxyaniline (commercially available, 0.250 g, 0.0011 mol)was added to TEA (0.234 mL, 0.0023 mol) in DCM (2.5 mL) and the mixturewas cooled to 0° C. To the mixture phenyl isocyanate (0.179 g, 0.0015mol) was added and the reaction mixture was stirred at 25° C. for 16 h.The solid material produced was filtered off and washed with n-pentane(5 ml) to yield 0.300 g (77% yield) of the title compound. This was usedin the next step without further purification. ¹H NMR (400 MHz, DMSO-d6)δ ppm 3.86 (s, 3H) 6.56 (app dd, 1H) 6.81 (app d, 1H) 6.92-7.02 (m, 3H)7.09 (app ft, 1H) 7.23-7.33 (m, 2H) 7.32-7.42 (m, 2H) 7.41-7.49 (m, 2H)8.08 (app d, 1H) 8.19 (s, 1H) 9.26 (s, 1H); MS (ES+) m/z 335 [M+H]⁺

Intermediate 12 1-(4-Morpholinophenyl)-3-(4-phenoxyphenyl)urea

4-(4-isocyanatophenyl)morpholine (commercially available, 0.500 g,0.0024 mol) was added to a solution of 4-phenoxyaniline (commerciallyavailable, 0.340 g, 0.0018 mol) and TEA (0.380 g, 0.0037 mol) in DCM(5.0 mL) at 0° C. The reaction mixture was allowed to come to 25° C. andstirred for 16 h. The reaction mixture was quenched with ice-water (50ml) and product extracted with DCM (3×40 ml). The combined organiclayers were washed with brine (30 ml), dried over sodium sulfate andevaporated under reduced pressure to obtain the crude product. The crudeproduct was purified on silica gel (100-200 mesh) using 1.5% methanol indichloromethane as an eluent to obtain 0.080 g (11% yield) of the titlecompound. MS (ES+) m/z 390 [M+H]⁺

Intermediate 13 1-(3-methoxy-4-phenoxyphenyl)-3-phenylurea

In a 50 ml RBF previously equipped with a magnetic stirrer phenylisocyanate (0.297 g, 0.0024 mol) was added to a solution of3-methoxy-4-phenoxyaniline (commercially available, 0.450 g, 0.0020 mol)and TEA (0.406 mL, 0.0040 mol) in DCM (4.50 mL) at 0° C. The resultingreaction mixture was allowed to reach 25° C. and stirred for 2 h. Thesolvent was evaporated under reduce pressure to obtain 0.500 g of crudeproduct. This was used in the next step without further purification. ¹HNMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3H) 6.76-6.85 (m, 2H) 6.91-7.06(m, 4H) 7.29 (app ddt, 4H) 7.46 (app ddd, 3H) 8.69 (s, 1H) 8.77 (s, 1H).

Intermediate 14 1-(3-cyano-4-phenoxyphenyl)-3-phenylurea

Phenyl isocyanate (0.373 g, 0.0017 mol) was added to a solution of5-amino-2-phenoxybenzonitrile (commercially available, 0.600 g, 0.0015mol) and TEA (0.521 ml, 0.0023 mol) in DCM (6.00 mL) at 0° C. Thereaction mixture was stirred at 25° C. for 16 h. The solid produced wasfiltered to obtain the solid. The obtained solid was stirred inn-pentane (10 ml) for 15 min and the n-pentane was filtered off to yield0.330 g (35% yield) of the solid title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.00 (app t, 1H) 7.12-7.01 (m, 2H) 7.10 (app t, 1H)7.17-7.26 (m, 1H) 7.25-7.34 (m, 2H) 7.39-7.50 (m, 4H) 7.66 (app dd, 1H)8.01 (app d, 1H), 8.80 (s, 1H) 8.96 (s, 1H); MS (ES+) m/z 330 [M+H]⁺

Intermediate 15 1-methoxy-4-methyl-2-nitro-5-phenoxybenzene

To a solution of taken Phenol (0.200 g, 0.0021 mol) in DMF (2.0 mL) in aseal tube flask, NaH (0.056 g, 0.0023 mol) was added portion wise at 0°C. under N₂ (g). The reaction mixture was stirred for 1 hour.1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (0.432 g, 0.0023 mol) wasadded portion wise and the reaction mixture was stirred at 120° C. for 5h. The reaction mixture was quenched with ice-water (15 ml) andextracted with Diethyl ether (3×20 ml). The combined organic layers waswashed with brine (30 ml). Organic layer was dried over sodium sulfateand evaporated under reduced pressure to obtain crude product. The crudeproduct was purified on combi flash chromatography by using 20% Ethylacetate in Hexane as a mobile phase and 60-120 silica to yield 0.550 gof the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.18 (s, 3H) 2.74(s, 3H) 6.63-6.76 (m, 1H) 6.95 (app dt, 2H) 6.98-7.11 (m, 3H) 8.47 (s,1H).

Intermediate 16 2-methoxy-5-methyl-4-phenoxyaniline

1-methoxy-4-methyl-2-nitro-5-phenoxybenzene (Intermediate 15, 0.540 g,0.00208 mol) and SnCl₂.2H₂O (1.870 g, 0.0833 mol) were dissolved inEthanol (5.40 mL) and cooled to 0° C. 35% HCl (0.540 mL) was added andthe reaction mixture was stirred at 50° C. for 5 h. The reaction mixturewas diluted with ethyl acetate (50 ml) and basified with 30% aqueousammonia solution to maintain pH 7-8. The precipitate was filteredthrough a celite pad and washed with ethyl acetate (3×5 ml). Thefiltrate was washed with H₂O (3×40 ml) and brine (40 ml). Organic layerwas dried over sodium sulfate and evaporated under reduce pressured toobtain 0.450 g of the title compound which was used without furtherpurification in the next step. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91 (s,3H) 3.71 (s, 3H) 4.59 (s, 2H) 6.52 (app d, 2H) 6.72-6.81 (m, 2H)6.92-7.01 (m, 1H) 7.23-7.33 (m, 2H).

Intermediate 17 1-(2-methoxy-5-methyl-4-phenoxyphenyl)-3-phenylurea

2-methoxy-5-methyl-4-phenoxyaniline (Intermediate 16, 0.440 g, 0.00191mol) and TEA (0.400 mL, 0.00287 mol) were dissolved in DCM (4.50 mL)cooled to 0° C. Phenyl isocyanate (0.251 g, 0.00211 mol) was added andthe resulting reaction mixture was stirred at 25° C. for 16 h. The solidproduced was filtered off and filtered to obtain the solid. The obtainedsolid was stirred with n-pentane (15 ml) for 15 min and the n-pentanewas filtered off to yield 0.285 g (43% yield) of the solid titlecompound which was used in the next step without further purification.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.04 (s, 3H) 3.81 (s, 3H) 6.72 (s, 1H)6.80-6.88 (m, 2H) 7.00 (app dt, 2H) 7.24-7.38 (m, 4H) 7.42-7.50 (m, 2H)8.07 (s, 1H) 8.19 (s, 1H) 9.28 (s, 1H).

Intermediate 18 1-methoxy-3-methyl-5-nitro-2-phenoxybenzene

2-methoxy-6-methyl-4-nitrophenol (0.230 g, 0.0012 mol) and phenylboronic acid (0.336 g, 0.0027 mol) were dissolved in DCM (11.9 mL) with4 Å molecular sieves (11.5 g) at 25° C. under N₂ (g). The reactionmixture was cooled to 0° C. and TEA (0.881 mL, 0.0062) was addedfollowed by the addition of calcium acetate (0.228 g, 0.0012 mol). Thereaction mixture was stirred for 6 h at 0° C. then allowed to come to25° C. and stirred for 16 h. The reaction mixture was filtered through acelite pad and washed with DCM (2×40 ml). The filtrate was washed withwater (2×15 ml) followed by the washing with brine (20 ml), dried oversodium sulfate and evaporated under reduced pressure to obtained thecrude product. The crude product was purified on silica gel (60-120mesh) using 10% ethyl acetate in hexane as an eluent to obtained 0.340 gof the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.21 (s, 3H) 3.81(s, 3H) 6.76-6.83 (m, 2H) 6.97-7.09 (m, 1H) 7.32-7.26 (m, 2H) 7.82 (d,1H) 7.93 (dd, 1H).

Intermediate 19 3-methoxy-5-methyl-4-phenoxyaniline

HCl (35%) (0.34 mL) was added drop wise under stirring to a solution of1-methoxy-3-methyl-5-nitro-2-phenoxybenzene (Intermediate 18, 0.340 g,0.0013 mol) and SnCl₂.2H₂O (1.18 g, 0.0052 mol) in ethanol at 0° C.under N₂ (g). The reaction mixture was allowed to come to 25° C. andthen heated at 50° C. for 4 h. The reaction mixture was allowed to coolto room temperature and diluted with ethyl acetate (50 ml) and basifiedusing ammonia solution up to pH 7-8. The product was extracted in ethylacetate (2×30 ml). The combine organic layer was washed with brine (50ml), dried over sodium sulfate and evaporated under reduce pressure toobtained 0.290 g (97% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.91 (s, 3H) 3.59 (s, 3H) 6.05 (d, 1H) 6.20 (d, 1H)6.66-6.81 (m, 2H) 6.91 (m, 1H) 7.18-7.30 (m, 2H); MS (ES+) m/z 230[M+H]⁺

Intermediate 20 1-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-phenylurea

In a 10 ml seal tube previously equipped with a magnetic stirrer andnitrogen balloon, phenyl isocyanate (0.190 ml, 0.00099 mol) was addeddrop wise to a solution of 3-methoxy-5-methyl-4-phenoxyaniline(Intermediate 19, 0.190 g, 0.00082 mol) and TEA (0.232 mL, 0.0016 mol)in DCM (2.0 mL) at 0° C. The reaction mixture was allowed to reach 25°C. and stirred for 16 h. The reaction mixture was concentrated underreduced pressure to obtained crude product. The crude product waspurified on combi flash using 50% ethyl acetate in hexane as an eluentto yield 0.100 g (34% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.04 (s, 3H) 3.67 (s, 3H) 6.69-6.78 (m, 2H) 6.86-7.02 (m,3H) 7.22-7.33 (m, 5H) 7.42-7.50 (m, 2H) 8.71 (app d, 2H); MS (ES+) m/z349 [M+H]⁺

Intermediate 21 2-(cyclopentyloxy)-4-nitro-1-phenoxybenzene

Phenol (0.325 g, 0.0034 mol) dissolved in DMF (9.00 mL), in a 30 ml sealtube previously equipped with a magnetic stirrer and nitrogen balloon,was cooled to 0° C. NaH (0.113 g, 0.0047 mol) was added portion wise andstirred for 1 h. 1-bromo-2-(cyclopentyloxy)-4-nitrobenzene (commerciallyavailable, 0.900 g, 0.0031 mol) was added portion wise and the reactionmixture was stirred at 120° C. for 16 h. The reaction mixture wasquenched with ice-water (50 ml) and extracted with ethyl acetate (3×40ml). The combined organic layers were washed with brine (30 ml). Organiclayer was dried over sodium sulfate and evaporated under reducedpressure. The crude product was purified on column chromatography using20% ethyl acetate in hexane as a mobile phase and 60-120 silica to yield0.550 g (59% yield) of the title product. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.59-1.75 (m, 4H) 1.79-2.05 (m, 4H) 4.80-4.90 (m, 1H) 6.93-7.09 (m,3H) 7.10-7.21 (m, 1H) 7.31-7.42 (m, 2H) 7.81-7.91 (m, 2H).

Intermediate 22 3-(cyclopentyloxy)-4-phenoxyaniline

2-(cyclopentyloxy)-4-nitro-1-phenoxybenzene (Intermediate 21, 0.500 g,0.0016 mol) SnCl₂.2H₂ (1.50 g, 0.0066 mol) were dissolved in ethanol(5.0 mL) and cooled to 0° C. HCl (35%, 0.50 mL) was added and thereaction mixture was stirred at 50° C. for 5 h. The reaction mixture wasdiluted with ethyl acetate (20 ml) and basified with 30% aqueous ammoniasolution to maintain pH 7-8. The obtained solid was filtered anddiscarded. The filtrate was washed with H₂O (3×15 ml) and brine (20 ml).Organic layer was dried over sodium sulfate and evaporated under reducedpressure to yield 0.480 g of the title compound which was used withoutfurther purification in the next step.

Intermediate 23 1-[3-(cyclopentyloxy)-4-phenoxyphenyl]-3-methylurea

3-(cyclopentyloxy)-4-phenoxyaniline (Intermediate 22, 0.240 g, 0.00089mol) and TEA (0.135 ml, 0.00130 mol) were dissolved in DCM (2.50 mL) andto 0° C. N-Methyl formyl chloride (0.099 g, 0.00100 mol) was added andthe resulting reaction mixture was stirred at 25° C. for 16 h. Thesolvent was evaporated and the reaction mixture was quenched with water(10 ml) and product was extracted with ethyl acetate (3×30 ml). Thecombined organic layer was washed with brine (30 ml). Organic layer wasdried over sodium sulfate and evaporated under reduced pressure toobtain crude product. The crude product was purified on Combi flashchromatography using 1% MeOH in DCM as a mobile phase and 60-120 silicaas stationary phase to yield 0.180 g (62% yield) of the title compound.MS (ES+) m/z 327 [M+H]⁺

Intermediate 24 1-(3-ethoxy-4-phenoxyphenyl)-3-phenylurea

In a 30 ml seal tube previously equipped with a magnetic stirrer andnitrogen balloon, phenyl isocyanate (0.226 mL, 0.0019 mol) was addeddrop wise to the solution of 3-ethoxy-4-phenoxyaniline (0.400 g, 0.0017mol) and TEA (0.489 mL, 0.0034 mol) in DCM (4.0 mL) at 0° C. Thereaction mixture was allowed to slowly reach 25° C. and stirred for 16h. The solvent was evaporated under reduced pressure to obtain the crudeproduct. The crude product was purified on silica gel (60-120 mesh)using 30% ethyl acetate in hexane as an eluent to obtain 0.230 g (38%yield) of the title compound. H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t,3H) 3.94-4.04 (m, 2H) 6.79-6.86 (m, 1H) 6.87-7.01 (m, 1H) 7.11-7.20 (m,1H) 7.24-7.34 (m, 4H) 7.39-7.50 (m, 6H) 8.62-8.69 (m, 1H) 8.72 (s, 1H);MS (ES+) m/z 349 [M+H]⁺

Intermediate 25 3-(5-nitro-2-phenoxyphenoxy)tetrahydrofuran

In a 30 ml seal tube flask previously equipped with a magnetic stirrerand nitrogen balloon, NaH (0.109 g, 0.0045 mol) was added portion wiseto a solution of Phenol (0.391 g, 0.0041 mol) in DMF (12 mL) at 0° C.and stirred for 1 h. 3-(2-bromo-5-nitrophenoxy)tetrahydrofuran(commercially available, 1.200 g, 0.0041 mol) was added portion wise andthe reaction mixture was stirred at 120° C. for 16 h. The reactionmixture was quenched with ice-water (50 ml) and product extracted withethyl acetate (3×40 ml). The combined organic layers were washed withbrine (30 ml). The organic layer was dried over sodium sulfate andevaporated under reduced pressure to obtain crude product. The crudeproduct was purified on column chromatography using 20% Ethyl acetate inhexane as a mobile phase on 60-120 silica to yield 0.900 g (76% yield)of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (m, 1H) 2.19(m, 1H) 3.56-3.66 (m, 1H) 3.68-3.79 (m, 2H) 3.85-3.95 (m, 1H) 5.25 (m,1H) 7.01-7.12 (m, 3H) 7.16-7.23 (m, 1H) 7.38-7.48 (m, 2H) 7.85-7.94 (m,2H).

Intermediate 26 4-phenoxy-3-(tetrahydrofuran-3-yloxy)aniline

in a u ml I-previously-equipped with a magnetic stirrer 35% HCl in water(0.30 mL) was added to a solution of3-(5-nitro-2-phenoxyphenoxy)tetrahydrofuran (Intermediate 25, 0.90 g,0.0029 mol) and SnCl₂.2H₂O (2.69 g, 0.0011 mol) in ethanol (20 mL) at 0°C. The reaction mixture was stirred at 50° C. for 5 h. The reactionmixture was diluted with ethyl acetate (50 ml) and basified with 30%aqueous ammonia solution to maintain pH 7-8. The precipitate wasfiltered through a celite pad and washed with ethyl acetate (3×5 ml).The filtrate was washed with water (3×40 ml) followed by washing withbrine (40 ml), dried over sodium sulfate and evaporated under reducedpressure to yield 0.750 g (85% yield) the title compound that was usedwithout further purification in the next step. ¹H NMR (400 MHz, DMSO-d6)δ 1.70-1.82 (m, 1H) 1.94-2.08 (m, 1H) 3.39-3.51 (m, 1H) 3.55-3.83 (m,2H) 3.80-3.95 (m, 1H) 5.04 (s, 1H) 6.17 (dd, 1H) 6.32 (d, 1H) 6.75 (m,3H) 6.82-6.98 (m, 1H) 7.11-7.29 (m, 2H).

Intermediate 271-[4-Phenoxy-3-(tetrahydrofur-3-yloxy)phenyl]-3-phenylurea

In a 50 ml RBF previously equipped with a magnetic stirrer phenylisocyanate (0.144 g, 0.0011 mol) was added to a solution of4-phenoxy-3-(tetrahydrofuran-3-yloxy)aniline (Intermediate 26

Intermediate 28 1-(3-methyl-4-phenoxyphenyl)-3-pyridin-2-ylurea

In a 50 ml RBF previously equipped with a magnetic stirrer was taken3-methyl-4-phenoxyaniline (commercially available, 0.500 g, 0.0025 mol)and NaHCO₃ (0.63 g, 0.0075 mol) were added to DCM (5.0 mL) and cooled to0° C. To the mixture, triphosgene (0.491 g, 0.0016 mol) was added andthe resulting reaction mixture was stirred at 0° C. for 4 h. 2-aminopyridine (0.236 g, 0.0025 mol) and NaHCO₃ (0.63 g, 0.0075 mol) wereadded to the reaction mixture. The resulting reaction mixture wasstirred at 25° C. for 16 h. The solvent was evaporated and the reactionmixture was quenched with water (25 ml) and product was extracted withDCM (3×30 ml). The combined organic layer was washed with brine (30 ml).The organic layer was dried over sodium sulfate and evaporated underreduced pressure to obtain a crude product. The crude product waspurified by using 0.02% ammonia as a modifier and water:acetonitrile(0-100% gradient system) as a mobile phase in preparative HPLCpurification to yield 0.4 g (50% yield) of the title compound. ¹H NMR(400 MHz, DMSO-d6) δ ppm 2.13 (s, 3H) 6.84-6.93 (m, 4H) 6.99-7.07 (m,3H) 7.31-7.48 (m, 3H) 7.77 (m, 1H) 8.29 (m, 1H) 9.47 (s, 1H) 10.50 (s,1H); MS (ES+) m/z 320 [M+H]⁺

Intermediate 29 1-phenyl-3-(1-phenyl-1H-indazol-5-yl)urea

Phenyl isocyanate was added to a solution of 1-phenyl-1H-indazol-5-amine(commercially available, 0.187 g, 0.0008 mol) and TEA (0.240 mL, 0.0017mol) in DCM (1.80 mL) at 0° C. The resulting reaction mixture wasallowed to reach 25° C. and stirred for 16 h. The solvent was evaporatedunder reduced pressure to obtain a crude product. The crude product waspurified on silica gel (60-120 mesh) using 2% ethyl acetate in hexane asan eluent to yield 0.150 g (92% yield) of the title compound. H NMR (400MHz, DMSO-d6) δ ppm 6.98 (m, 1H) 7.25-7.34 (m, 2H), 7.35-7.46 (m, 1H)7.48 (m, 3H) 7.55-7.65 (m, 2H) 7.74-7.85 (m, 3H) 8.07 (d, 1H) 8.32 (d,1H) 8.67 (s, 1H) 8.79 (s, 1H); MS (ES+) m/z 329 [M+H]⁺

Intermediate 30 1-(3-ethoxy-4-phenoxyphenyl)-3-methylurea

In a 30 ml seal tube previously equipped with a magnetic stirrer andnitrogen balloon, methylaminoformyl chloride (0.090 g, 0.00095 mol) wasadded drop wise to a solution of 3-ethoxy-4-phenoxyaniline (0.20 g,0.00087 mol) and TEA (0.244 mL, 0.0017 mol) in DCM (2.0 ml) at 0° C. Thereaction mixture was allowed to reach 25° C. and stirred for 16 h. Thesolvent was evaporated under reduced pressure to obtain a crude product.The crude product was purified on silica gel (60-120 mesh) using 3%methanol in dichloromethane as an eluent to yield 0.093 g (37% yield) ofthe title compound. H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (m, 3H) 2.62 (s,3H) 3.94 (m, 2H) 6.76-7.02 (m, 4H) 7.03-7.15 (m, 2H) 7.23-7.32 (m, 2H)7.36 (s, 1H) 8.46 (s, 1H); MS (ES+) m/z 287 [M+H]⁺

Intermediate 311-methyl-3-[4-phenoxy-3-(tetrahydrofuran-3-yloxy)phenyl]urea

Methylaminoformyl chloride (0.075 g, 0.0008 mol) was added to a solutionof 4-phenoxy-3-(tetrahydrofuran-3-yloxy)aniline (Intermediate 26, 0.200g, 0.0007 mol) and TEA (0.115 mL, 0.0011 mol) in DCM (2.0 mL) at 0° C.The reaction mixture was allowed to reach 25° C. and stirred for 16 h.The reaction mixture was quenched with water (25 ml) and extracted withethyl acetate (3×30 ml). The combined organic layers were washed withbrine (30 ml), dried over sodium sulfate and evaporated under reducedpressure to obtain the crude product. The crude product was purified onsilica gel (60-120 mesh) using 90% ethyl acetate in hexane as an eluentto yield 0.120 g (66% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.78 (m, 1H) 2.05 (m, 1H) 2.63 (s, 3H) 3.48 (m, 1H) 3.56(m, 1H) 3.64 (m, 1H) 3.79 (m, 1H) 4.87 (m, 1H) 6.80 (m, 2H) 6.90 (m, 2H)6.92-7.02 (m, 2H) 7.23-7.32 (m, 2H) 7.35 (s, 1H) 8.56 (s, 1H).

Intermediate 32 1-[3-(Cyclopentyloxy)-4-phenoxyphenyl]-3-phenylurea

Phenyl isocyanate (0.126 g, 0.0010 mol) was added to a solution of3-(cyclopentyloxy)-4-phenoxyaniline (Intermediate 22, 0.240 g, 0.0008mol) and TEA (0.135 mL, 0.0013 mol) in DCM (2.50 mL) at 0° C. Theresulting reaction mixture was stirred at 25° C. for 16 h. The solventwas evaporated and the reaction mixture was quenched with water (25 ml)and product extracted with ethyl acetate (3×30 ml). The combined organiclayers were washed with brine (30 ml). The organic layer was dried oversodium sulfate and evaporated under reduced pressure to obtain the crudeproduct. The crude product was purified on combi flash chromatography byusing 5% MeOH in DCM as a mobile phase and 60-120 silica as stationaryphase to yield 0.125 g (58% yield) of the title compound.

Intermediate 33 3-[(2-bromo-5-nitrophenoxy)methyl]oxetane

In RB flask previously equipped with a magnetic stirrer and nitrogenballoon, DEAD (1.298 g, 0.0064 mol) was added drop wise to a solution of2-bromo-5-nitrophenol (0.700 g, 0.0032 mol), oxetan-3-ylmethanol (0.310g, 0.0035 mol) and triphenyl phosphine (1.685 g, 0.0062 mol) in THF (7.0mL) at 0° C. The reaction mixture was stirred at 25° C. for 16 h. Thereaction mixture was evaporated under reduced pressure to obtain thecrude product. The crude product was purified on column chromatographyon 100-200 silica by using 15% ethyl acetate in hexane as a mobile phaseto yield 1.3 g (quantitative yield) of the title compound that wasdirectly used in the next step. ¹H NMR (400 MHz, DMSO-d6) δ ppm3.39-3.52 (m, 1H) 4.39-4.44 (m, 2H) 4.45-4.52 (m, 2H) 4.67-4.75 (m, 2H)7.72-7.80 (m, 1H) 7.89-7.95 (m, 2H).

Intermediate 34 3-[(5-nitro-2-phenoxyphenoxy)methyl]oxetane

In a 30 ml seal tube flask previously equipped with a magnetic stirrerand nitrogen balloon, NaH (0.030 g, 0.0012 mol) was added portion wiseto the solution of Phenol (0.119 g, 0.0012 mol) in DMF (2.80 mL) at 0°C. After stirring for 1 h, 3-[(2-bromo-5-nitrophenoxy)methyl]oxetane(Intermediate 33, 0.280 g, 0.0009 mol) was added portion wise and thereaction mixture was stirred at 120° C. for 16 h. The reaction mixturewas quenched with ice-water (50 ml) and extracted with ethyl acetate(3×40 ml). The combined organic layers were washed with brine (30 ml).The organic layer was dried over sodium sulfate and evaporated underreduced pressure to obtain crude product. The crude product was purifiedon column chromatography by 15% ethyl acetate in hexane as a mobilephase and 60-120 silica as the stationary phase to yield 0.160 g (62%yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.29 (m,1H) 4.25 (m, 2H) 4.36 (m, 2H) 4.60-4.41 (m, 2H) 6.99-7.07 (m, 2H)7.09-7.24 (m, 2H) 7.36-7.46 (m, 2H) 7.87-7.96 (m, 1H) 7.99 (d, 1H).

Intermediate 35 3-(oxetan-3-ylmethoxy)-4-phenoxyaniline

10% Pd/C (0.042 g) was added to a solution of3-[(5-nitro-2-phenoxyphenoxy)methyl]oxetane (Intermediate 34, 0.160 g,0.0005 mol) in methanol (1.60 mL) at 25° C. The resulting reactionmixture was stirred for 16 h under a hydrogen balloon. The reactionmixture was filtered through a celite bed, which was washed with MeOH(3×10 ml). The filtrate was evaporated under reduced pressure to obtain0.100 g (66% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δppm 3.14 (m, 1H) 3.98-4.11 (m, 4H) 4.35-4.46 (m, 2H) 5.06 (s, 2H) 6.18(dd, J=8.4, 2.4 Hz, 1H) 6.38 (d, J=2.5 Hz, 1H) 6.71-6.81 (m, 3H) 6.93(m, 1H) 7.19-7.28 (m, 2H); MS (ES+) m/z 272 [M+H]⁺

Intermediate 36 1-methyl-3-[3-(oxetan-3-ylmethoxy)-4-phenoxyphenyl]urea

Methylaminoformyl chloride (0.041 g, 0.00043 mol) was added to asolution of 3-(oxetan-3-ylmethoxy)-4-phenoxyaniline (Intermediate 35,0.041 g, 0.00037 mol) and TEA (0.103 ml, 0.0007 mol) in DCM (1.0 mL) at0° C. The reaction mixture was stirred at 25° C. for 16 h. The solventwas evaporated under reduced pressure to obtain the crude product. Thecrude product was purified on chromatography by using 0-5% MeOH in DCM(gradient) as a mobile phase and 60-120 silica as stationary phase toproduce 0.120 g of the title compound in quantitative yield. ¹H NMR (400MHz, DMSO-d6) δ ppm 2.65 (d, 1H) 3.19-3.03 (m, 2H) 4.15-4.04 (m, 3H)4.43 (m, 2H) 5.75 (m, 2H) 6.04 (s, 1H) 6.78 (m, 2H) 7.02-6.86 (m, 3H)7.27 (m, 2H) 7.41 (s, 1H) 8.62 (s, 1H); MS (ES+) m/z 329 [M+H]⁺

Intermediate 37 1-{3-[(3-Oxetanyl)methoxy]-4-phenoxyphenyl}-3-phenylurea

Phenyl isocyanate (0.283 mL, 0.0025 mol)) was added to a solution of3-(oxetan-3-ylmethoxy)-4-phenoxyaniline (Intermediate 35, 0.640 g,0.0023 mol) and TEA (0.662 mL, 0.0047 mol) in DCM (6.4 mL) understirring at 0° C. The reaction mixture was stirred at 25° C. for 16 h.The solvent was evaporated under reduced pressure to obtain the crudeproduct. The crude product was purified on column chromatography byusing 70% ethyl acetate in hexane as a mobile phase and 60-120 silica asstationary phase to produce 0.840 g of the title compound inquantitative yield. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (m, 1H) 4.11(m, 4H) 4.44 (m, 2H) 6.78-6.85 (m, 2H) 6.87-7.08 (m, 4H) 7.29-7.39 (m,4H) 7.41-7.50 (m, 3H) 8.68 (s, 1H) 8.75 (s, 1H); MS (ES+) m/z 391 [M+H]⁺

Intermediate 38 4-nitro-1-phenoxy-2-(propan-2-yloxy)benzene

NaH (0.153 g, 0.0063 mol) was added portion wise to a solution of Phenol(0.119 g, 0.0012 mol) stirred in DMF (8.30 mL) under N₂ (g) and cooledat 0° C. After 1 h stirring, 1-Bromo-2-isopropoxy-4-nitrobenzene(commercially available, 0.830 g, 0.0031 mol) was added portion wise andthe reaction mixture was heated at 120° C. for 16 h. The reactionmixture was quenched with ice-water (50 ml) and extracted with ethylacetate (3×40 ml). The combined organic layers were washed with brine(30 ml), dried over sodium sulfate and the solvent was evaporated underreduced pressure. The crude product was purified on silica gel (60-120mesh) using 20% ethyl acetate in hexane as an eluent to obtain 0.638 g(79% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.23(d, 6H) 4.79 (m, 1H) 6.98-7.13 (m, 2H) 7.12-7.25 (m, 1H) 7.28-7.38 (m,1H) 7.37-7.47 (m, 2H) 7.81-7.94 (m, 2H).

Intermediate 39 4-phenoxy-3-(propan-2-yloxy)aniline

35% HCl (0.6 mL) was added to a solution of4-nitro-1-phenoxy-2-(propan-2-yloxy)benzene (Intermediate 38, 0.638 g,0.0024 mol) and SnCl₂.2H₂O (2.490 g, 0.0098 mol) in ethanol (6 mL) at 0°C. The reaction mixture was allowed to slowly reach 25° C. and thenheated at 50° C. for 3 h. The reaction mixture was diluted with ethylacetate (50 ml) and basified with 30% aqueous ammonia to maintained pH7-8. The precipitate was filter through celite pad and washed with ethylacetate (2×10 ml). The filtrate was washed with water (3×40 ml) followedby the washing with brine (40 ml), dried over sodium sulfate and thesolvent evaporated under reduce pressure to obtain 0.510 g (76% yield)of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (m, 6H) 4.40(m, 1H) 4.95 (s 2H) 6.00-6.19 (m, 1H) 6.35 (d, 1H) 6.69-6.81 (m, 1H)6.82-6.99 (m, 1H) 6.99-7.19 (m, 2H) 7.19-7.28 (m, 2H); MS (ES+) m/z 244[M+H]⁺

Intermediate 40 1-methyl-3-[4-phenoxy-3-(propan-2-yloxy)phenyl]urea

Methylaminoformyl chloride (0.074 ml, 0.0008 mol) was added to asolution of 4-phenoxy-3-(propan-2-yloxy)aniline (Intermediate 39, 0.200g, 0.0007 mol) and TEA (0.205 mL, 0.0014 mol) in DCM (2 mL) understirring at 0° C. The reaction mixture was stirred at 25° C. for 16 h.The solvent was evaporated under reduced pressure to obtain crudeproduct. The crude product was purified on silica gel (60-120 mesh)using 2% methanol in dichloromethane as an eluent to obtain 0.103 g (41%yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.32(m, 6H) 4.35-4.55 (m, 1H) 2.61 (s, 3H) 6.75-7.02 (m, 4H) 7.02-7.15 (m,2H) 7.27 (m, 2H) 7.37 (s, 1H) 8.53 (s, 1H); MS (ES+) m/z 301 [M+H]⁺

Intermediate 41 1-[4-phenoxy-3-(propan-2-yloxy)phenyl]-3-phenylurea

Phenyl isocyanate (0.143 mL, 0.0012 mol) was added to a solution of4-phenoxy-3-(propan-2-yloxy)aniline (Intermediate 39, 0.300 g, 0.0010mol) and TEA (0.307 mL, 0.0021 mol) in DCM (3 mL) under stirring at 0°C. The reaction mixture was allowed to reach 25° C. and stirred for 16h. The solvent was evaporated under reduced pressure. The crude productwas purified on silica gel (60-120 mesh) using 2% methanol indichloromethane as an eluent to yield 0.103 g (53% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.37 (m, 6H) 4.51 (m, 1H)6.76-6.92 (m, 1H) 6.89-7.05 (m, 3H) 7.11-7.19 (m, 1H) 7.24-7.33 (m, 4H)7.40-7.50 (m, 4H), 8.60-8.73 (brs, 2H); MS (ES+) m/z 363 [M+H]⁺

Intermediate 42 2-(2-methoxyethoxy)-4-nitro-1-phenoxybenzene

In a 30 ml seal tube previously equipped with a magnetic stirrer andnitrogen balloon, NaH (0.109 g, 0.0045 mol) was added portion wise to asolution of Phenol (0.224 g, 0.0022 mol) in DMF (6.3 mL) cooled at 0° C.After 1 h, 1-bromo-2-(2-methoxyethoxy)-4-nitrobenzene (commerciallyavailable, 0.630 g, 0.0022 mol) was added portion wise and the reactionmixture was heated at 120° C. for 16 h. The reaction mixture wasquenched with ice-water (50 ml) and extracted with ethyl acetate (3×40ml). The combined organic layers were washed with brine (30 ml), driedover sodium sulfate and evaporated under reduced pressure to obtain thecrude product. The crude product was purified on silica gel (60-120mesh) using 10% ethyl acetate in hexane as an eluent to yield 0.450 g(68% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d6) δ 3.35 (s, 3H) 3.70-3.77 (m, 2H) 4.32-4.39 (m,2H) 7.76 (m, 3H) 7.85-7.94 (m, 5H).

Intermediate 43 3-(2-methoxyethoxy)-4-phenoxyaniline

35% HCl_((aq)) (0.30 mL) and water (0.1 mL) were added to a solution of2-(2-methoxyethoxy)-4-nitro-1-phenoxybenzene (Intermediate 42, 0.450 g,0.0015 mol) and SnCl₂.2H₂O (1.400 g, 0.0062 mol) in ethanol understirring at 0° C. The reaction mixture was allowed to reach 25° C. andthen heated at 50° C. for 3 h. The reaction mixture was diluted withethyl acetate (50 ml) and basified with 30% aqueous ammonia to maintainpH 7-8. The precipitate was filter through celite pad and washed withethyl acetate (2×10 ml). The filtrate was washed with water (3×40 ml)and brine (40 ml), dried over sodium sulfate and evaporated underreduced pressure to obtain 0.310 g (77% yield) of the title compoundwhich was used directly in the next step without further purification.¹H NMR (400 MHz, DMSO-d6) δ ppm 3.13 (s, 3H) 3.41-3.48 (m, 2H) 3.86-3.97(m, 2H) 5.04 (s, 2H) 6.16 (m, 1H) 6.36 (d, 1H) 6.70-6.81 (m, 3H)6.83-6.98 (m, 1H) 7.20-7.29 (m, 2H); MS (ES+) m/z 260 [M+H]⁺

Intermediate 44 1-[3-(2-methoxyethoxy-4-phenoxyphenyl]-3-methylurea

Methylaminoformyl chloride (0.056 g, 0.0006 mol) was added to a solutionof 3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.180 g,0.0005 mol) and TEA (0.130 mL, 0.0010 mol) in DCM (1.30 mL) at 0° C. Thereaction mixture was stirred at 25° C. for 16 h. The solvent wasevaporated under reduced pressure and the crude product was purified onsilica gel (60-120 mesh) using 50% ethyl acetate in hexane as an eluentto 0.063 g (28% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6))δ ppm 2.62-2.66 (m, 3H) 3.15 (s, 3H) 3.44-3.50 (m, 2H) 3.95-4.05 (m, 2H)6.01 (m, 1H) 6.77-6.84 (m, 2H) 6.86-6.94 (m, 2H) 6.95-7.01 (m, 1H)7.23-7.31 (m, 2H) 7.36 (s, 1H) 8.52 (s, 1H); MS (ES+) m/z 317 [M+H]⁺

Intermediate 45 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-phenylurea

Phenyl isocyanate (0.090 g, 0.0007 mol) was added to a solution of3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.180 g, 0.0006mol) and TEA (0.140 mL, 0.0010 mol) in DCM (2.0 mL) under stirring at 0°C. The reaction mixture was stirred at 25° C. for 16 h. The solvent wasevaporated and the reaction mixture was quenched with water (25 ml) andextracted with ethyl acetate (3×30 ml). The combined organic layers werewashed with brine (30 ml). The organic layer was dried over sodiumsulfate and evaporated under reduced pressure to obtain crude product.The crude product was purified on silica gel (60-120 mesh) using 50%ethyl acetate in hexane as an eluent to obtain 0.135 g (51% yield) ofthe title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.13 (s, 3H)3.43-3.52 (m, 2H) 4.00-4.09 (m, 2H) 6.79-6.87 (m, 2H) 6.90-7.03 (m, 4H)7.20-7.35 (m, 4H) 7.39-7.50 (m, 3H) 8.67 (s, 1H), 8.72 (s, 1H); MS (ES+)m/z 379 [M+H]⁺

Intermediate 46 2-(benzyloxy)-4-nitro-1-phenoxybenzene

In a 30 ml seal tube previously equipped with a magnetic stirrer andnitrogen balloon, NaH (0.046 g, 1.95 mmol) was added portion wise to asolution of Phenol (0.183 g, 1.95 mmol) in DMF (6.0 mL) cooled at 0° C.After 1 hour, benzyl 2-bromo-5-nitrophenyl ether (commerciallyavailable, 0.600 g, 1.95 mmol) was added portion wise and the reactionmixture was heated at 120° C. for 16 h. The reaction mixture wasquenched with ice-water (50 ml) and extracted with ethyl acetate (3×40ml). The combined organic layers were washed with brine (30 ml), driedover sodium sulfate and evaporated under reduced pressure. The crudeproduct was purified on silica gel (60-120 mesh) using 20% ethyl acetatein hexane as an eluent to obtained 0.386 g (82% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 5.29 (s, 2H) 7.03-7.14 (m, 3H)7.22 (m, 1H) 7.27-7.40 (m, 5H) 7.39-7.48 (m, 2H) 7.90 (m, 1H) 8.05 (m,1H); MS (ES+) m/z 322 [M+H]⁺

Intermediate 47 3-(benzyloxy)-4-phenoxyaniline

35% HCl_((aq)) (0.35 ml) was added to a solution of2-(benzyloxy)-4-nitro-1-phenoxybenzene (Intermediate 46, 0.386 g, 1.2012mmol) and SnCl₂.2H₂O (0.854 g, 3.788 mmol) in ethanol under stirring at0° C. The reaction mixture was heated at 50° C. for 5 h. The reactionmixture was diluted with ethyl acetate (50 ml) and basified with 30%aqueous ammonia to maintain pH 7-8. The mixture was filtered throughcelite pad and washed with ethyl acetate (3×5 ml). The filtrate waswashed with water (3×40 ml) and with brine (40 ml), dried over sodiumsulfate and evaporated under reduced pressure to obtain 0.330 g of thetitle compound in quantitative yield. ¹H NMR (400 MHz, DMSO-d6) δ ppm5.06 (s, 2H) 5.15 (s, 2H) 6.18 (m, 1H) 6.43 (m, 1H) 6.56-6.70 (m, 1H)6.72-6.88 (m, 2H) 6.85-7.00 (m, 1H) 7.08-7.21 (m, 2H) 7.21-7.31 (m, 3H)7.31-7.51 (m, 2H); MS (ES+) m/z 292 [M+H]⁺

Intermediate 48 1-[3-(benzyloxy)-4-phenoxyphenyl]-3-methylurea

Methylaminoformyl chloride (0.036 g, 0.386 mmol) was added to a solutionof 3-(benzyloxy)-4-phenoxyaniline (Intermediate 47, 0.125 g, 0.429 mmol)and TEA (0.060 mL, 0.429 mmol) in DCM (2.0 mL) under stirring at 0° C.The reaction mixture was stirred at 25° C. for 16 h. The reactionmixture was quenched with water (20 ml) and extracted with DCM (3×30ml). The combined organic layers were washed with brine (30 ml), driedover sodium sulfate and evaporated under reduced pressure. The crudeproduct was purified on silica gel (60-120 mesh) using 100% ethylacetate as an eluent to obtained 0.100 g (67% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.97 (s, 3H) 5.05 (s, 2H) 6.17(m, 1H) 6.42 (m, 1H) 6.73-6.84 (m, 3H) 6.91-7.00 (m, 1H) 7.08-7.17 (m,2H) 7.19-7.32 (m, 5H) 7.62 (s, 1H) 8.56 (s, 1H); MS (ES+) m/z 349 [M+H]⁺

Intermediate 49 1-methyl-3-(1-phenyl-1H-indazol-5-yl)urea

Methylaminoformyl chloride (0.100 g, 0.0010 mol) was added to a stirredsolution of 1-phenyl-1H-indazol-5-amine (commercially available, 0.187g, 0.0008 mol) and TEA (0.240 ml, 0.0017 mol) in DCM (1.80 mL) at 0° C.The reaction mixture was stirred at 25° C. for 16 h. The solvent wasevaporated under reduced pressure. The crude product was purified onsilica gel (60-120 mesh) using 50% ethyl acetate in hexane as an eluentto yield 0.085 g (35% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d6) δ 2.66 (s, 3H) 6.00 (m, 1H) 7.32-7.41 (m, 2H) 7.53-7.61 (m, 2H)7.73-7.78 (m, 3H) 8.00 (s, 1H) 8.26 (s, 1H) 8.61 (s, 1H).

Intermediate 50 1-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-methylurea

In a 10 ml seal tube flask previously equipped with a magnetic stirrerand nitrogen balloon, methylaminoformyl chloride (0.048 ml, 0.0052 mol)was added portion wise to a solution of3-methoxy-5-methyl-4-phenoxyaniline (Intermediate 19, 0.100 g, 0.00043mol) and TEA (0.122 mL, 0.00087 mol) in DCM (1.0 mL) at 0° C. Thereaction mixture was stirred for 16 hours at 25° C. The reaction mixturewas concentrate under reduced pressure to obtain the crude product. Thecrude product was purified on silica gel using 10% methanol indichloromethane as an eluent to 0.080 g (66% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.00 (s, 3H) 3.18 (s, 3H) 3.63(s, 3H) 6.05 (s, 1H) 6.68-6.75 (m, 1H) 6.82 (m, 2H) 6.94 (m, 2H)7.18-7.30 (m, 2H) 8.57 (s, 1H); MS (ES+) m/z 287 [M+H]⁺

Intermediate 51 2-methoxy-3-methyl-1-nitro-4-phenoxybenzene

In a 30 ml seal tube previously equipped with a magnetic stirrer andnitrogen balloon, NaH (0.273 g, 0.0113 mol) was added portion wise to asolution of Phenol (0.588 g, 0.0062 mol) in DMF (14.0 mL) cooled at 0°C. After 1 hour, 1-bromo-3-methoxy-2-methyl-4-nitrobenzene (commerciallyavailable, 1.40 g, 0.0056 mol) was added portion wise and then thereaction mixture was heated at 120° C. for 16 h. The reaction mixturewas quenched with ice-water (50 ml) and extracted with ethyl acetate(3×40 ml). The combined organic layers were washed with brine (30 ml),dried over sodium sulfate and evaporated under reduce pressure to obtaincrude product. The crude product was purified on silica gel (60-120mesh) using 5% ethyl acetate in hexane as an eluent to yield 0.815 g(55% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.26(s, 3H) 3.87 (s, 3H) 7.20-7.07 (m, 2H) 7.34-7.21 (m, 1H) 7.52-7.42 (m,2H) 7.81 (m, 1H) 7.93 (d, 1H).

Intermediate 52 2-methoxy-3-methyl-4-phenoxyaniline

35% HCl_((aq)) (0.80 mL) was added to a solution of2-methoxy-3-methyl-1-nitro-4-phenoxybenzene (Intermediate 51, 0.815 g,0.0031 mol) and SnCl₂.2H₂O (2.83 g, 0.0120 mol) in ethanol (10.0 mL)under stirring at 0° C. The resulting reaction mixture was heated at 50°C. for 3 h. The reaction mixture was diluted with ethyl acetate (50 ml)and basified with 30% aqueous ammonia to maintain pH 7-8. The mixturewas filtered through a celite pad and washed with ethyl acetate (2×5ml). The filtrate were washed with water (3×40 ml) followed by washingwith brine (40 ml), dried over sodium sulfate and evaporated underreduced pressure to yield 0.715 g of the title compound. MS (ES+) m/z230 [M+H]⁺

Intermediate 53 1-(2-methoxy-3-methyl-4-phenoxyphenyl)-3-phenylurea

Phenyl isocyanate (0.446 g, 0.0037 mol) was added to a solution of2-methoxy-3-methyl-4-phenoxyaniline (Intermediate 52, 0.715 g, 0.0031mol) and TEA (0.875 mL, 0.0062 mol) in DCM (7.10 mL) under stirring at0° C. The resulting reaction mixture was stirred at 25° C. for 16 h. Thereaction mixture was quenched with water (25 ml) and extracted withethyl acetate (3×30 ml). The combined organic layers were washed withbrine (30 ml), dried over sodium sulfate and evaporated under reducedpressure to yield 0.394 g (36% yield) of the title compound. ¹H NMR (400MHz, DMSO-d6) δ ppm 2.09 (s, 3H) 3.75 (s, 3H) 6.73 (d, 1H) 6.86 (m, 2H)6.97 (m, 1H) 7.05 (m, 1H) 7.25-7.38 (m, 4H) 7.47 (m, 2H) 8.04 (d, 1H)8.33 (s, 1H) 9.30 (s, 1H); MS (ES+) m/z 349 [M+H]⁺

Intermediate 54 1-[3-methyl-4-(phenylsulfanyl)phenyl]-3-phenylurea

Phenyl isocyanate (1.05 g, 0.0088 mol) was added to a solution of3-methyl-4-(phenylsulfanyl)aniline (commercially available, 1.74 g,0.0080 mol) and TEA (2.27 mL, 0.0161 mol) in DCM (17.4 mL) understirring at 0° C. The reaction mixture was stirred at 25° C. for 16 h.The solvent was evaporated and the reaction mixture was quenched withwater (25 ml) and extracted with Ethyl Acetate (3×30 ml). The combinedorganic layers were washed with brine (25 ml). The organic layer wasdried over sodium sulfate and evaporated under reduced pressure toobtain the crude product. The crude product was purified on columnchromatography by using 15% ethyl acetate in hexane as a mobile phaseand 100-200 silica as stationary phase to yield 1.10 g (40% yield) ofthe title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H)6.93-7.08 (m, 3H) 7.12-7.21 (m, 1H) 7.26-7.36 (m, 4H) 7.38 (m, 2H)7.41-7.53 (m, 3H) 8.74 (s, 1H) 8.83 (s, 1H); MS (ES+) m/z 335 [M+H]⁺

Intermediate 55 3-methyl-5-nitro-1-phenyl-1H-indole

To a solution of 3-methyl-5-nitro-1H-indole (commercially available,0.500 g, 0.0028 mol) in 1,4-dioxane (5.0 mL) was added dry cesiumcarbonate (2.770 g, 0.0085 mol) followed by the addition of Iodobenzene(0.753 g, 0.0036 mol) at 0° C. After 10 minutes of degassing with argongas, X-phos (0.270 g, 0.00056 mol) and Pd(OAc)₂ (0.063 g, 0.00028 mol)were added under argon atmosphere. The reaction mixture was heated at110° C. for 16 h under argon atmosphere. The reaction mixture wasquenched with ice-water (30 ml) and extracted with ethyl acetate (3×25ml). The combined organic layers were washed with brine (20 ml), driedover sodium sulfate and concentrated under reduce pressure to obtaincrude product. The crude product was purified on silica gel (60-120mesh) using 2% ethyl acetate in hexane as an eluent to yield 0.430 g(56% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.33(s, 3H) 7.40-7.50 (m, 2H) 7.58-7.80 (4H) 8.02-8.11 (m, 2H) 8.60 (d, 1H);MS (ES+) m/z 253 [M+H]⁺

Intermediate 56 3-methyl-1-phenyl-1H-indol-5-amine

To a solution of 3-methyl-5-nitro-1-phenyl-1H-indole (Intermediate 55,0.430 g, 0.0017 mol) in ethanol (4.30 mL) SnCl₂.2H₂O (1.538 g, 0.0068mol) was added followed by the addition of 35% HCl (0.430 mL) at 0° C.The reaction mixture was heated at 50° C. for 5 h. The reaction mixturewas diluted with ethyl acetate (40 ml) and basified with 30% ammoniaaqueous solution. The precipitated was filtered and washed with ethylacetate (3×25 ml). The combined organic layer was washed with water(3×20 ml) and brine (20 ml), dried over sodium sulfate and the solventwas evaporated under reduced pressure. The crude product was purified onbasic alumina oxide using 40% ethyl acetate in hexane as an eluent toyield 0.200 g (55% yield) of the title compound. MS (ES+) m/z 223 [M+H]⁺

Intermediate 57 1-(3-methyl-1-phenyl-1H-indol-5-yl)-3-phenylurea

To a solution of 3-methyl-1-phenyl-1H-indol-5-amine (Intermediate 56,0.200 g, 0.0009 mol) in DCM (3.00 mL), sodium bicarbonate (0.23 g,0.0027 mol) was added followed by addition of Triphosgene (0.176 g,0.00059 mol) at 0° C. under nitrogen atmosphere. After stirring for 4 hat 0° C., aniline (0.092 g, 0.00099 mol) and sodium bicarbonate (0.23 g,0.0027 mol) were added at 0° C. under nitrogen atmosphere. The resultingreaction mixture was allowed reach 25° C. and stirred for 16 hours. Thereaction mixture was quenched with water (25 ml) and extracted withdichloromethane (3×30 ml). The combined organic layer was washed withbrine (30 ml), dried over sodium sulfate and the solvent evaporatedunder reduced pressure to yield 0.310 g (quantitative yield) of thetitle compound that was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H) 6.91-7.01 (m,1H) 7.11-7.16 (m, 1H), 7.23-7.37 (m, 3H), 7.42-7.51 (m, 4H) 7.53-7.58(m, 3H) 7.68-7.81 (m, 2H) 8.61 (s, 1H) 8.69 (s, 1H); MS (ES+) m/z 342[M+H]⁺

Intermediate 58 1-benzyl-3-methyl-5-nitro-1H-indole

To a solution of 3-methyl-5-nitro-1H-indole (commercially available,1.00 g, 0.0056 mol) in DMF (10.0 mL) was added potassium tert-butoxide(0.764 g, 0.0068 mol) at 0° C. After 20 min of stirring at 0° C.,benzylbromide (0.970 g, 0.0056 mol) was added dropwise and the reactionmixture was allowed to slowly reach 25° C. and stirred for 18 h undernitrogen atmosphere. The reaction mixture was quenched with ice-water(50 ml) and extracted with ethyl acetate (3×40 ml). The combined organiclayer was washed with brine (30 ml), dried over sodium sulfate and thesolvent evaporated under reduced pressure. The crude product waspurified using flash chromatography on silica gel (60-120 mesh) using10% ethyl acetate in hexane as eluent to yield 0.935 g (62% yield) ofthe title compound. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 2.33 (s, 3H). 5.46(s, 2H), 7.35-7.20 (m, 5H), 7.53 (s, 1H), 7.65 (d, 1H), 8.00 (dd, 1H),8.50 (d, 1H). MS (ES+) m/z 267 [M+H]⁺

Intermediate 59 1-benzyl-3-methyl-1H-indol-5-amine

To a solution of 1-benzyl-3-methyl-5-nitro-1H-indole (Intermediate 58,0.0081 mol) in ethanol (9.30 mL) was added SnCl₂.2H₂O (3.151 g, 0.0326mol) followed by the addition of 35% HCl (0.930 mL) at 0° C. Thereaction mixture was heated at 50° C. for 5 h. The reaction mixture wasdiluted with ethyl acetate (50 ml) and basified with 30% ammonia aqueoussolution. The precipitated was filtered off and washed with ethylacetate (3×5 ml). The combined organic layer was washed with water (3×40ml) followed by the washing with brine (40 ml), dried over sodiumsulfate and the solvent evaporated under reduce pressure. The crudeproduct was purified on flash chromatography with basic alumina oxideusing 50% ethyl acetate in hexane as an eluent to obtained 0.630 g (71%yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 2.11 (s,3H) 4.45 (s, 2H) 5.71 (s, 2H) 6.44 (d, 1H) 6.59 (s, 1H) 7.07-6.99 (m,2H) 7.10-7.13 (m, 2H) 7.18-7.28 (m, 3H); MS (ES+) m/z 237 [M+H]⁺

Intermediate 60 1-(1-benzyl-3-methyl-1H-indol-5-yl)-3-phenylurea

To a solution of 1-benzyl-3-methyl-1H-indol-5-amine (Intermediate 59,0.300 g, 0.0012 mol) in DCM (3.00 mL) was added TEA (0.356 mL, 0.0025mol) followed by the addition of phenyl isocyanate (0.166 g, 0.0013 mol)to 0° C. under nitrogen atmosphere. The reaction mixture was allowed toreach at 25° C. and stirred for 16 h. The solid obtained was filteredoff and retained. The obtained solid was stirred in n-pentane (10 mL)for 15 min. The solid was filtered of and washed with n-pentane (5 mL)to obtain 0.425 g (94% yield) of the solid title compound. The compoundwas used in the next step without further purification. ¹H NMR (400 MHz,DMSO-d6) δ ppm 2.25 (s, 3H) 5.31 (s, 2H) 6.91-6.99 (m, 1H) 7.02 (dd, 1H)7.16-7.19 (m, 2H) 7.20-7.32 (m, 7H) 7.45 (app d, 2H) 7.67 (d, 1H) 8.43(s, 1H) 8.56 (s, 1H); MS (ES+) m/z 356 [M+H]⁺

Intermediate 61 1-methyl-3-(3-methyl-1-phenyl-1H-indol-5-yl)urea

To a solution of 3-methyl-1-phenyl-1H-indol-5-amine (Intermediate 56,0.150 g, 0.00067 mol) in DCM (1.50 ml) was added sodium bicarbonate(0.172 g, 0.0020 mol) followed by addition of triphosgene (0.132 g,0.00044 mol) at 0° C. under nitrogen atmosphere. After stirring for 4 hat 0° C., 33% methylamine solution in EtOH (0.069 mL, 0.00074 mol) andsodium bicarbonate (0.172 g, 0.0020 mol) were added. The reactionmixture was allowed to reach 25° C. and stirred for 16 h. The reactionmixture was quenched with water (15 ml) and extracted withdichloromethane (3×20 ml). The combined organic layer was washed withbrine (15 ml), dried over sodium sulfate and the solvent was evaporatedunder reduce pressure to yield 0.070 g (37% yield) of the title compoundthat was used in the next step without further purification. MS (ES+)m/z 280 [M+H]⁺

Intermediate 62 1-(1-benzyl-3-methyl-1H-indol-5-yl)-3-methylurea

To a solution of 1-benzyl-3-methyl-1H-indol-5-amine (Intermediate 59,0.480 g, 0.0020 mol) in DCM (4.80 mL) cooled to 0° C. and under N₂(g),TEA (0.410 mL, 0.0040 mol) was added under stirring followed by additionof N-methylformyl chloride (0.187 g, 0.0020 mol). The reaction mixturewas allowed to reach 25° C. and stirred for 16 h.

The solid precipitates were filtered off and washed with n-pentane (10ml) to yield 0.230 g (38%) of the title compound. The crude product wasused in the next step without further purification. MS (ES+) m/z 294[M+H]+

Intermediate 63 1-(3-chloro-4-phenoxyphenyl)-3-phenylurea

A solution of 3-chloro-4-phenoxyaniline (commercially available, 1.2 g,0.0054 mol) and TEA (1.53 ml, 0.0109 mol) in DCM (12 ml) was stirred at0° C. Phenyl isocyanate (0.781 g, 0.0065 mol) was added and theresulting reaction mixture was allowed to reach 25° C. and stirred for16 h. The solvent was removed under reduced pressure and the reactionmixture was quenched with ice-water (30 ml). The resulting solution wasextracted with Ethyl Acetate (3×40 ml) and the combined organic layerwas washed with brine (30 ml). The organic layer was dried over sodiumsulfate and evaporated under reduced pressure to obtain the crudeproduct. The crude product was purified by column chromatography onsilica gel (100-200 mesh) using 40% ethyl acetate in hexanes as aneluent to obtain 1.19 g (64%) of the title compound. ¹H NMR (400 MHz,DMSO-d6) δ ppm 6.86-6.97 (m, 2H) 6.99 (t, J=7.6 Hz, 1H) 7.04-7.16 (m,2H) 7.24-7.41 (m, 5H) 7.42-7.50 (m, 2H) 7.86 (d, J=2.6 Hz, 1H) 8.76 (s,1H) 8.90 (s, 1H); MS (ES+) m/z 339 [M+H]+

Intermediate 641-(3-methyl-4-phenoxyphenyl)-3-(5-methylthiophen-2-yl)urea

A solution of 5-methyl-2-thiophenamine (0.670 g, 0.0045 mol),NaHCO₃(0.984 g, 0.0112 mol) in DCM (7.5 mL) was stirred at 0° C. To thereaction mixture, Triphosgene (0.722 g, 0.0024 mol) was added and theresulting reaction mixture was stirred at 0° C. for 4 hours. To thereaction mixture 3-methyl-4-phenoxyaniline (0.750 g, 0.0037 mol) andNaHCO₃ (0.984 g, 0.0112 mol) were added and the mixture was allowed toreach 25° C. and stirred for 16 hours. The solvent was evaporated andthe reaction mixture was diluted with water (30 ml) and the product wasextracted with ethyl acetate (3×40 m). The combined organic layer waswashed with brine (30 ml) and dried over sodium sulphate and evaporatedunder reduced pressure to obtain the crude product. The crude productwas purified on combi-flash chromatography using 50% ethyl acetate inhexanes as an eluent to obtain 1.07 g (84% yield) of the title compound.¹H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H), 2.33 (S, 3H), 6.33 (d,J=3.6 Hz, 1H), 6.48 (d, J=3.5, 1.4 Hz, 1H), 6.93-6.81 (m, 3H), 7.04 (t,J=7.3 Hz, 1H), 7.31 (m, 3H), 7.41 (d, J=2.6 Hz, 1H), 8.67 (s, 1H), 9.43(s, 1H); MS (ES+) m/z 339 [M+H]+

Intermediate 65 1-(4-fluorophenyl)-3-(3-methyl-4-phenoxyphenyl)urea

A mixture of 3-methyl-4-phenoxyaniline (0.375 g, 0.0018 mol), NaHCO₃(0.474 g, 0.0056 mol) in DCM (3.75 ml) was stirred and cooled to 0° C.Triphosgene (0.368 g, 0.0012 mol) was added and the resulting reactionmixture was stirred at 0° C. for 4 h. 4-fluro-aniline (0.209 g, 0.0018mol) and NaHCO₃ (0.474 g, 0.0056 mol) were added to the reaction mixtureand stirred at 25° C. for 16 h. The solvent was evaporated, and thereaction mixture was quenched with water (20 ml) and the product wasextracted with EtOAc (3×30 ml). The combined organic layer was washedwith brine (20 ml) and dried over sodium sulphate. The solvent wasevaporated under reduced pressure to obtain crude product. The crudeproduct was purified by Combi-flash chromatography using 40% ethylacetate in hexanes as an eluent to obtain 0.110 g (17% yield) of thetitle compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H), 6.81-6.93(m, 3H), 6.99-7.13 (m, 1H), 7.14 (d, J=8.9 Hz, 2H), 7.25-7.38 (m, 4H),7.39-7.52 (m, 2H), 8.63 (s, 1H), 8.69 (s, 1H); MS (ES+) m/z 337 [M+H]+

Intermediate 66 1-(benzofuran-5-yl)-3-(3-methyl-4-phenoxyphenyl)urea

Benzofuran-5-amine (10 mg, 0.08 mmol) and triphosgene (7.5 mg, 0.02mmol) were dissolved in 2 ml DCM and the solution was cooled to 0° C.Triethylamine (21 μl, 0.15 mmol) was added and the solution was stirredat 0° C. for 1 h. A solution of 3-methyl-4-phenoxy-aniline (16.5 mg,0.08 mmol) and trimethylamine (21 μl, 0.15 mmol) in DCM (0.25 ml) wasadded. The reaction mixture was allowed to reach RT and the reaction wasleft to stir overnight. The reaction was quenched with 0.5 ml of H₂O.NH4Cl (aq. sat) and DCM were added and the water phase was extractedfurther with DCM (×3). The solid present in the combined organic phaseswas filtered off. The solution was dried over MgSO₄ and concentrated atreduced pressure to yield 0.026 g (96% yield) of the title compound thatwas used without further purification in the next step. MS (ESI+) m/z359 (M+H)+

Intermediate 67 1-(1H-indol-5-yl)-3-(3-methyl-4-phenoxyphenyl)urea

1H-indol-5-amine (50 mg, 0.38 mmol) and triphosgene (37 mg, 0.12 mmol)were dispersed in 5 ml DCM and the solution was cooled to 0° C.Triethylamine (105 μl, 0.76 mmol) was added and the mixture was stirredat 0° C. for 1.5 h. A solution of 3-methyl-4-phenoxy-aniline (83 mg,0.42 mmol) and trimethylamine (105 μl, 0.76 mmol) in 0.5 ml DCM was thenadded. The reaction mixture was allowed to reach room temperature andwas stirred for 4 h. The reaction was quenched with 0.5 ml of H₂O. NH4Cl(aq sat.) and DCM were added and the water phase was extracted furtherwith DCM (×3). The combined organic phases were concentrated at reducedpressure and dried at 35° C. under vacuum overnight. The product wasdissolved in DCM/MeOH solvent mix and was concentrated onto silica. Itwas purified by column chromatography (Isolera, Biotage silica column 25g) eluting with gradients of MeOH in DCM (0-4.5%) to yield 69 mg (51%yield) of title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H),8.51 (s, 1H), 8.37 (s, 1H), 7.68 (d, J=1.9 Hz, 1H), 7.43 (d, J=2.4 Hz,1H), 7.37-7.25 (m, 5H), 7.07 (dd, J=8.7, 2.0 Hz, 1H), 7.03 (t, J=7.4 Hz,1H), 6.88 (d, J=8.7 Hz, 1H), 6.86-6.81 (m, 2H), 6.38-6.32 (m, 1H), 2.11(s, 3H). MS (ESI+) m/z 358 (M+H)+

Intermediate 681-(1,3-benzodioxol-5-yl)-3-(3-methyl-4-phenoxyphenyl)urea

1,3-benzodioxol-5-amine (83 mg, 0.61 mmol) and triphosgene (54 mg, 0.18mmol) were dispersed in 10 ml DCM and the solution was cooled to 0° C.Triethylamine (0.15 ml, 1.1 mmol) was added and the mixture was stirredat 0° C. for 1.5 h. A solution of 3-methyl-4-phenoxy-aniline (110 mg,0.55 mmol) and triethylamine (0.15 ml, 1.1 mmol) in 1 ml DCM was added.The reaction mixture was allowed to reach room temperature and stirredfor 2 h. The reaction was quenched with H₂O. NH4Cl (aq. sat.) and DCMwere added and the phases were separated. The organic phase wasconcentrated at reduced pressure and further dried under vacuum at 40°C. for 3 h to yield 215 mg of the crude title compound that was usedwithout further purification the next step. MS(ESI+) m/z 363 (M+H)+

Intermediate 69 1-(1H-indol-4-yl)-3-(3-methyl-4-phenoxyphenyl)urea

1H-indol-4-amine (50 mg, 0.38 mmol) and triphosgene (37 mg, 0.12 mmol)were dispersed in 5 ml DCM and the solution was cooled to 0° C.Triethylamine (105 μl, 0.76 mmol) was added and the mixture was stirredat 0° C. for 1.5 h. A solution of 3-methyl-4-phenoxy-aniline (83 mg,0.42 mmol) and triethylamine (105 μl, 0.76 mmol) in 0.5 ml DCM wasadded. The reaction mixture was allowed to reach room temperature andstirred for 2 h. The reaction was quenched with H2O. NH4Cl (aq. sat.)and DCM were added and the phases were separated. The organic phase wasconcentrated at reduced pressure. The solid was washed with pentane anddried under vacuum at 35° C. to yield 118 mg of the crude title compoundthat was used without further purification in the next step. MS(ESI+)m/z 358 (M+H)+

Intermediate 70 1-(3-methoxyphenyl)-3-(3-methyl-4-phenoxyphenyl)urea

3-methoxyaniline (90 μl, 0.80 mmol) and triphosgene (79 mg, 0.26 mmol)were dispersed in 10 ml DCM and the solution was cooled to 0° C.Triethylamine (223 μl, 1.61 mmol) was added and the mixture was stirredat 0° C. After stirring the reaction mixture for a total of 1.5 h, asolution of 3-methyl-4-phenoxy-aniline (176 mg, 0.88 mmol) andtriethylamine (223 μl, 1.61 mmol) in 1 ml DCM was added. The solutionwas allowed to reach room temperature and the reaction mixture was leftat RT overnight. The reaction was quenched with H2O. NH4Cl (aq. sat.)and DCM were added and the phases were separated, the organic phase wasdried over MgSO4. The solution was thereafter divided in half and wasconcentrated at reduced pressure, dried under vacuum at 30° C. overnightand further purified by column chromatography (Grace 40 g column,Biotage Isolera) eluting with gradients of MeOH in DCM (0-5%) to yield115 mg (36% yield) of the title compound. MS(ESI+) m/z 349 (M+H)+

Intermediate 71 1-(2-methoxyphenyl)-3-(3-methyl-4-phenoxyphenyl)urea

2-methoxyaniline (99 μl, 0.88 mmol) and triphosgene (87 mg, 0.29 mmol)were dispersed in 10 ml DCM and the solution was cooled to 0° C.Triethylamine (243 μl, 1.75 mmol) was added and the mixture was stirredat 0° C. After stirring the reaction mixture for a total of 1.5 h, asolution of 3-methyl-4-phenoxy-aniline (192 mg, 0.96 mmol) andtriethylamine (243 μl, 1.75 mmol) in 1 ml DCM was added. The solutionwas allowed to reach room temperature and was left to stir a RTovernight. The reaction was quenched with H₂O. NH4Cl (aq. sat.) and DCMwere added and the phases were separated, the organic phase was driedover MgSO₄. The solution was thereafter divided equally into 2 vials andwas concentrated at reduced pressure. Half of the material taken out,concentrated at reduced pressure and dried under vacuum at 30° C.overnight and further purified by column chromatography (Grace 40 gcolumn, Biotage Isolera) eluting with gradients of MeOH in DCM (0-5%) toyield 119 mg (35% yield) of the title compound. MS(ESI+) m/z 349 (M+H)+

Intermediate 72 1-(3-methoxy-4-phenoxyphenyl)-3-(3-methoxyphenyl)urea

3-methoxyaniline (108 mg, 0.88 mmol) and triphosgene (87 mg, 0.29 mmol)were dispersed in 10 ml DCM and the solution was cooled to 0° C.Triethylamine (243 μl, 1.75 mmol) was added and the mixture was stirredat 0° C. for 1.5 h. 3-Methoxy-4-phenoxy-aniline (207 mg, 0.96 mmol) andtriethylamine (243 μl, 1.75 mmol) were dissolved in DCM (1 ml) and wasadded to the mixture. The mixture was stirred at RT over night. Thereaction mixture was quenched with H₂O. NH4Cl (aq. sat.) and DCM wereadded and the phases were separated, the organic phase was dried overMgSO4. The solution was concentrated at reduced pressure and the productwas purified by column chromatography (Biotage Isolera, 80 g silicacolumn) eluting with gradients of MeOH in DCM (0 to 5%) to yield 225 mg(70% yield) of the title compound. MS(ESI+) m/z 365 (M+H)+

Intermediate 73 1-(3-methoxy-4-phenoxyphenyl)-3-(4-methoxyphenyl)urea

4-Methoxyaniline (108 mg, 0.88 mmol) and triphosgene (87 mg, 0.29 mmol)were dispersed in 10 ml DCM and the solution was cooled to 0° C.Triethylamine (243 μl, 1.75 mmol) was added and the mixture was stirredat 0° C. for 1.5 h. 3-methoxy-4-phenoxy-aniline (207 mg, 0.96 mmol) andtriethylamine (243 μl, 1.75 mmol) were dissolved in DCM (1 ml) and wasadded to the mixture. The mixture was stirred at RT over night. Thereaction mixture was quenched with H2O. NH4Cl (aq. sat.) and DCM wereadded and the phases were separated. The organic phase was dried overMgSO4 and concentrated at reduced pressure. The crude was dissolved inDCM/MeOH and was evaporated onto silica. The product/silica mix wasapplied to a silica column and the product was purified by columnchromatography (Biotage Isolera, 80 g silica column) eluting withgradients of MeOH in DCM (0 to 5%) to yield 288 mg (90% yield) of thetitle compound. MS(ESI+) m/z 365 (M+H)+

Intermediate 74 1-(4-benzyl-3-methylphenyl)-3-phenylurea

4-benzyl-3-methylaniline (0.70 g, 0.0035 mol) and TEA (0.99 ml) in DCM(7.0 ml) was stirred at 0° C. To the mixture, Phenyl isocyanate (0.63 g,0.0053 mol) was added and the resulting reaction mixture was allowed toreach 25° C. and stirred for 16 h. The reaction was quenched withmixture of ice-water (20 ml). Product was extracted with DCM (3×30 ml)and the combined organic layer was washed with brine (20 ml). Theorganic layer was dried over sodium sulphate and evaporated underreduced pressure to obtain the crude product. The crude product waspurified by column chromatography on silica gel (100-200 mesh) using 20%ethyl acetate in hexanes as an eluent to obtain 0.6 g (53% yield) of thetitle compound. MS(ESI+) m/z 317 (M+H)+

Intermediate 75 1-(3-chlorophenyl)-3-(3-methyl-4-phenoxyphenyl)urea

3-methyl-4-phenoxy-aniline (0.50 g, 0.0025 mol) NaHCO₃ (0.63 g, 0.0075mol) in DCM (5.0 ml) was stirred and cooled to 0° C. Triphosgene (0.29g, 0.0010 mol) was added to the mixture and it was stirred for 4 h.3-Chloro aniline and NaHCO₃ ((0.63 g, 0.0075 mol)) were added. Theresulting reaction mixture was stirred at 25° C. for 16 h. The solventwas evaporated under reduced pressure and the reaction mixture wasquenched with water (30 ml) and product was extracted with EtOAc (3×40ml). The combined organic layer was washed with brine (30 ml) and driedover sodium sulphate and evaporated under reduced pressure to obtaincrude product. The crude product was purified by Combi-flashchromatography using 20% ethyl acetate in hexanes as an eluent to yield0.470 g (53% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δppm 8.88 (s, 1H), 8.72 (s, 1H), 7.77-7.68 (m, 1H), 7.44 (d, J=2.6 Hz,1H), 7.38-7.23 (m, 5H), 7.08-6.98 (m, 2H), 6.88 (dd, J=20.6, 8.3 Hz,3H), 2.12 (s, 3H); MS(ESI+) m/z 353 (M+H)+

Intermediate 761-(3-methyl-4-phenoxyphenyl)-3-[3-(trifluoromethoxy)phenyl]urea

3-methyl-4-phenoxy-aniline (0.5 g, 0.0025 mol) and NaHCO₃ (0.63 g,0.0075 mol) was added to DCM (5.0 ml) and stirred at 0° C. Triphosgene(0.29 g, 0.0010 mol) was added and the resulting reaction mixture wasstirred at 0° C. for 4 h. 3-(trifluromethoxy)-aniline (0.44 g, 0.0025mol) and NaHCO₃(0.63 g, 0.0075 mol) were added. The resulting reactionmixture was stirred at 25° C. for 16 h. The solvent was evaporated andthe reaction mixture was quenched with water (25 ml) and product wasextracted with EtOAc (3×30 ml). The combined organic layer was washedwith brine (25 ml). The combined organic layer was dried over sodiumsulphate and evaporated under reduced pressure to obtain crude product.The crude product was purified by Combi-flash chromatography using 30%ethyl acetate in hexanes as an eluent to obtain 0.450 g (44% yield) ofthe title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (s, 1H), 8.73(s, 1H), 7.72 (s, 1H), 7.47-7.36 (m, 2H), 7.39-7.26 (m, 4H), 7.04 (t,J=7.3 Hz, 1H), 6.92 (dd, J=16.7, 8.5 Hz, 2H), 6.85 (d, J=8.0 Hz, 2H),2.13 (s, 3H); MS(ESI+) m/z 403 (M+H)+

Intermediate 77 1-(3-methyl-4-phenoxyphenyl)-3-(4-methylphenyl)urea

3-methyl-4-phenoxy-aniline (0.50 g, 0.0025 mol) and NaHCO₃ (0.63 g,0.0075 mol) was added to DCM (5.0 ml) and the mixture was cooled to 0°C. Triphosgene (0.49 g, 0.0016 mol) was added and the resulting reactionmixture was stirred at 0° C. for 4 h. p-Toluidine (0.26 g, 0.0025 mol)and NaHCO₃(0.63 g, 0.0075 mol) were added and resulting reaction mixturewas stirred at 25° C. for 16 h. The solvent was evaporated under reducedpressure and the reaction mixture was quenched with water (20 ml) andproduct was extracted with EtOAc (3×30 ml). The combined organic layerwas washed with brine (20 ml) and dried over sodium sulphate and thesolvent evaporated under reduced pressure to obtain crude product thatwas purified by Combi-flash chromatography using 30% ethyl acetate inhexanes as an eluent to yield 0.240 (28% yield) of the title compound.¹H NMR (400 MHz, DMSO-d6) δ ppm 8.61-8.47 (m, 2H), 7.37-7.25 (m, 6H),7.12-6.99 (m, 4H), 6.93-6.81 (m, 2H), 2.24 (s, 3H), 2.11 (s, 3H);MS(ESI+) m/z 333 (M+H)+

Intermediate 78 1-methyl-3-(3-methyl-4-phenoxyphenyl)urea

3-methyl-4-phenoxy-aniline (0.5 g, 0.0025 mol) and NaHCO₃ (0.63 g,0.0075 mol) was added to DCM (5.0 ml) and stirred at 0° C. Triphosgene(0.49 g, 0.0016 mol) was added and the reaction mixture was stirred at0° C. for 4 h. Methyl amine (33% in ethanol, 0.25 ml, 0.0025 mol) andNaHCO₃ (0.63 g, 0.0075 mol) were added and reaction mixture was stirredat 25° C. for 16 h. The reaction mixture was quenched with water (20 ml)and extracted with DCM (3×35 ml). The combined organic layer was washedwith brine (20 ml) and dried over sodium sulfate and the solventevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (100-200 mesh) using 30% ethylacetate in hexanes as an eluent to yield 0.350 g (54% yield) of thetitle compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 7.33-7.24(m, 4H), 7.03 (t, J=7.3 Hz, 1H), 6.84 (t, J=8.1 Hz, 3H), 5.99 (q, J=4.6Hz, 1H), 2.65 (d, J=4.6 Hz, 3H), 2.08 (s, 3H); MS(ESI+) m/z 257 (M+H)+

Intermediate 79 1-(2,5-dimethyl-4-phenoxyphenyl)-3-phenylurea

A solution of 2,5-dimethyl-4-phenoxyaniline (commercially available,1.40 g, 0.0065 mol) in DCM (14.0 ml) and TEA (1.84 ml, 0.0131 mol) wasstirred and cooled to 0° C. Phenyl Isocyanate (0.93 g, 0.0078 mol) wasadded and the reaction mixture was allowed to reach 25° C. and stirredfor 16 h. The obtained solid precipitates were filtered out and washedwith n-pentane (20 ml) to yield 1.3 g (59% yield) of the title compound.¹H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (s, 1H), 7.89 (s, 1H), 7.74 (s,1H), 7.40-7.52 (m, 2H), 7.22-7.38 (m, 4H), 7.04 (t, J=7.4 Hz, 1H), 6.97(t, J=7.3 Hz, 1H), 6.89-6.79 (m, 3H), 2.19 (s, 3H), 2.09 (s, 3H);MS(ESI+) m/z 333 (M+H)+

Intermediate 801-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methylphenyl)urea

A solution of 3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43,0.30 g, 0.0011 mol) and NaHCO₃ (0.29 g, 0.0035 mol) in DCM (3.0 ml) wasstirred and cooled to 0° C. Triphosgene (0.22 g, 0.0007 mol) was addedand the reaction mixture was stirred at 0° C. for 4 h. 4-methylaniline(0.16 g, 0.0015 mol) and NaHCO₃(0.29 g, 0.0035 mol) were added and thereaction mixture was stirred at 25° C. for 16 h. The solvent wasevaporated under reduced pressure and the reaction mixture was quenchedwith water (30 ml) and extracted with DCM (3×40 ml). The combinedorganic layer was washed with brine (30 ml) and dried over sodiumsulphate and evaporated under reduced pressure. The crude product waspurified by Combi-flash chromatography using 20% ethyl acetate inhexanes as an eluent to yield 0.210 g (46% yield) of the title compound.¹H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 1H), 8.56 (s, 1H), 7.41 (d,J=2.2 Hz, 1H), 7.38-7.24 (m, 4H), 7.09-7.12 (m, 2H), 6.97 (m, 3H),6.82-6.89 (m, 2H), 4.04 (t, J=4.6 Hz, 2H), 3.49 (t, J=4.6 Hz, 2H), 3.16(s, 3H), 2.25 (s, 3H); MS(ESI+) m/z 393 (M+H)+

Intermediate 811-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methylphenyl)urea

A solution of 3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43,0.50 g, 0.0019 mol) and NaHCO₃ (0.48 g, 0.0057 mol) in DCM (5.0 ml) wasstirred and cooled to 0° C. Triphosgene (0.37 g, 0.0012 mol) was addedand the reaction mixture was stirred at 0° C. for 4 h. 3-methylaniline(0.20 g, 0.0019 mol) and NaHCO₃(0.48 g, 0.0057 mol) were added and thereaction mixture was stirred at 25° C. for 16 h. The solvent was removedunder reduced pressure and the reaction mixture was quenched with water(40 ml) and the product was extracted with EtOAc (3×50 ml). The combinedorganic layer was washed with brine (40 ml) and dried over sodiumsulfate and evaporated under reduced pressure. The crude product waspurified by Combi-flash chromatography using 40% ethyl acetate inhexanes as an eluent to yield 0.30 g (39%) of the title compound. H NMR(400 MHz, DMSO-d6) δ ppm 8.71 (s, 1H), 8.60 (s, 1H), 7.44 (d, J=2.2 Hz,1H), 7.36-7.22 (m, 4H), 7.26-7.13 (m, 1H), 7.06-6.92 (m, 3H), 6.89-6.77(m, 3H), 4.06 (t, J=4.4 Hz, 2H), 3.51 (t, J=4.8 Hz, 2H), 3.17 (s, 3H),2.29 (s, 3H); MS(ESI+) m/z 393 (M+H)+

Intermediate 821-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-chlorophenyl)urea

A solution of 3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43,0.30 g, 0.0011 mol) and NaHCO₃ (0.29 g, 0.0034 mol) in DCM (3.0 ml) wasstirred and cooled to 0° C. Triphosgene (0.22 g, 0.0007 mol) was addedand the reaction mixture was stirred at 0° C. for 4 h. 3-chloroaniline(0.11 g, 0.0008 mol) and NaHCO₃(0.29 g, 0.0034 mol) were added and thereaction mixture was stirred at 25° C. for 16 h. The solvent was removedunder reduced pressure and the reaction mixture was quenched with water(100 ml) and extracted with EtOAc (3×50 ml). The combined organic layerwas washed with brine (50 ml) and dried over sodium sulfate and thesolvent evaporated under reduced pressure. The crude product waspurified by Combi-flash chromatography using 40% ethyl acetate inhexanes as an eluent to yield 0.120 g (25% yield) of the title compound.¹H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.81 (s, 1H), 7.73 (s,1H), 7.42 (s, 1H), 7.36-7.23 (m, 4H), 7.06-6.92 (m, 4H), 6.81-6.90 (m,2H), 4.05 (t, J=4.6 Hz, 2H), 3.50 (t, J=4.6 Hz, 2H), 3.16 (s, 3H);MS(ESI+) m/z 413 (M+H)+

Intermediate 831-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-chlorophenyl)urea

3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.30 g, 0.0011mol) and NaHCO₃ (0.29 g, 0.0034 mol) in DCM (3.0 m) was cooled understirring to 0° C. Triphosgene (0.22 g, 0.0007 mol) was added and theresulting reaction mixture was stirred at 0° C. for 4 h. 4-Chloroaniline(0.19 g, 0.0015 mol) and NaHCO₃(0.29 g, 0.0034 mol) were added and thereaction mixture was stirred at 25° C. for 16 h. The solvent wasevaporated under reduced pressure and the reaction mixture was quenchedwith water (30 ml) and extracted with DCM (3×45 ml). The combinedorganic layer was washed with brine (30 ml) and dried over sodiumsulfate and the solvent removed under reduced pressure. The crudeproduct was purified by Combi-flash chromatography using 22% ethylacetate in hexanes as an eluent to yield 0.230 g (48% yield) of thetitle compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1H), 8.77 (s,1H), 7.54-7.47 (m, 2H), 7.42 (d, J=2.1 Hz, 1H), 7.39-7.26 (m, 4H),7.06-6.93 (m, 3H), 6.80-6.90 (m, 2H), 4.05 (t, J=4.7 Hz, 2H), 3.51 (t,J=4.7 Hz, 2H), 3.17 (s, 3H); MS(ESI+) m/z 413 (M+H)+

Intermediate 841-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methoxyphenyl)urea

3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.50 g, 0.0019mol) and NaHCO₃ (0.48 g, 0.0057 mol) were added to DCM (5.0 ml) and themixture was stirred and cooled to 0° C. Triphosgene (0.37 g, 0.0012 mol)was added and the reaction mixture was stirred at 0° C. for 4 h.4-methoxyaniline (0.30 g, 0.0025 mol) and NaHCO₃ (0.48 g, 0.0057 mol)were added and the reaction mixture was stirred at 25° C. for 16 h. Thesolvent was evaporated and the reaction mixture was quenched with water(30 ml) and extracted with DCM (3×50 ml). The combined organic layer waswashed with brine (30 ml) and dried over sodium sulfate and concentratedunder reduced pressure. The crude product was purified by theCombi-flash chromatography using 30% ethyl acetate in hexanes as aneluent to yield 0.250 g (31% yield) of the title compound. ¹H NMR (400MHz, DMSO-d6) δ ppm 8.64 (s, 1H), 8.49 (s, 1H), 7.44-7.25 (m, 6H),7.05-6.81 (m, 8H), 4.05 (t, J=4.6 Hz, 2H), 3.73 (s, 3H), 3.50 (t, J=4.7Hz, 2H), 3.17 (s, 3H). MS(ESI+) m/z 409 (M+H)+

Intermediate 851-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methoxyphenyl)urea

3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.50 g, 0.0019mol) and NaHCO₃ (0.48 g, 0.0057 mol) in DCM (5.0 ml) was stirred andcooled to 0° C. Triphosgene (0.37 g, 0.0012 mol) was added and thereaction mixture was stirred at 0° C. for 4 h. 3-methoxyaniline (0.23 g,0.0019 mol) and NaHCO₃ (0.48 g, 0.0057 mol) were added and the reactionmixture was stirred at 25° C. for 16 h. The solvent was evaporated andthe reaction mixture was quenched with water (100 ml) and extracted withEtOAc (3×50 ml). The combined organic layer was washed with brine (50ml) and dried over sodium sulfate and concentrated under reduced. Thecrude product was purified by Combi-flash chromatography using 40% ethylacetate in hexanes as an eluent to yield 0.35 g (44% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (s, 1H), 8.69 (s, 1H),7.40 (d, J=2.1 Hz, 1H), 7.35-7.28 (m, 2H), 7.21-7.15 (m, 2H), 7.06-6.92(m, 4H), 6.85-6.80 (m, 2H), 6.57 (dd, J=8.2, 2.5 Hz, 1H), 4.06 (t, J=4.7Hz, 2H), 3.75 (s, 3H), 3.51 (t, J=4.6 Hz, 2H), 3.17 (s, 3H); MS(ESI+)m/z 409 (M+H)+

Intermediate 86 1-[3-methyl-4-(2-methylphenoxy)phenyl]-3-phenylurea

3-methyl-4-(2-methylphenoxy)aniline (commercially available, 0.25 g,0.0011 mol) was dissolved in DCM (2.5 ml) under stirring. TEA (0.32 ml,0.0023 mol) was added at 0° C. followed by the addition of phenylisocyanate (0.15 g, 0.0012 mol). Reaction mixture was allowed to reach25° C. and stirred for 16 h. The obtained solid precipitates werefiltered out and washed with n-pentane (15 ml) to yield 0.25 g (64%) ofthe title compound that was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.69-8.57 (m, 2H),7.50-7.39 (m, 3H), 7.28 (m, 4H), 7.13 (t, J=3.2 Hz, 1H), 7.04-6.93 (m,2H), 6.75 (d, J=8.7 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 2.27 (s, 3H), 2.16(s, 3H); MS(ESI+) m/z 333 (M+H)+

Intermediate 87 1-(3-methyl-4-phenoxyphenyl)-3-(1,3-thiazol-4-yl)urea

A solution of 1,3-Thiazole-4-carboxylic acid (0.50 g, 0.0038 mol) intoluene (5.0 ml) was stirred and cooled to 0° C. and TEA (1.63 ml,0.0116 mol) was added drop wise. To the resulting mixture diphenylphosphoryl azide (DPPA, 1.17 g, 0.0042 mol) was added dropwise andstirred at 0° C. for 1 h. 3-methyl-4-phenoxy-aniline (0.50 g, 0.0025mol) in toluene was added dropwise and resulting reaction mixture wasstirred at 110° C. for 16 h. The solvent was evaporated and the reactionmixture was quenched with water (40 ml) and extracted with EtOAc (3×50ml). The combined organic layer was washed with brine (40 ml) and driedover sodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by Combi-flash chromatography using 30% ethylacetate in hexanes as an eluent to yield 0.400 g (49% yield) the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.95 (d, J=2.2Hz, 1H), 8.78 (s, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.38-7.27 (m, 4H), 7.04(t, J=7.4 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.89-6.79 (m, 2H), 2.12 (s,3H). MS(ESI+) m/z 326 (M+H)+

Intermediate 88 1-[4-(4-chlorophenoxy)phenyl]-3-methylurea

In a microwave vial previously equipped with a magnetic stirrer andnitrogen balloon, triethylamine (0.383 g, 0.0027 mol) was added dropwise to a solution of 4-(4-chlorophenoxy)aniline (0.300 g, 0.0045 mol)and N-methyl formyl chloride (0.125 g, 0.0045 mol) in DCM (3.0 ml) at 0°C. The reaction mixture was allowed to reach 25° C. and stirred for 16h. The reaction mixture was quenched with ice-water (50 ml) andextracted with ethyl acetate (3×40 ml). The combined organic layer waswashed with brine (30 ml), dried over sodium sulfate and the solventremoved under reduced pressure. The crude product was purified on silicagel (60-120 mesh) using 10% methanol in dichloromethane as an eluent toyield 0.130 g (34% yield) of the title compound.

Intermediate 89 1-(3-Chloro-4-phenoxyphenyl)-3-methylurea

3-Chloro-4-phenoxyaniline (commercially available, 0.340 g, 0.0015 mol)dissolved in DCM (3.4 ml) was stirred and cooled to 0° C. Triethylamine(0.435 ml, 0.0030 mol) followed by N-methyl formyl chloride (0.144 g,0.0015 mol) were added at 0° C. under nitrogen atmosphere. The reactionmixture was allowed reach 25° C. and stirred for 16 h. The solvent wasremoved under reduced pressure and the mixture was diluted with water(20 ml). The aqueous layer was extracted with EtOAc (3×25 ml). Thecombined organic layer was washed with brine (20 ml) and dried oversodium sulfate. The solvent was removed under reduced pressure and thecrude product was purified on combi-flash chromatography using 50% Ethylacetate in hexanes as an eluent to yield 0.150 g (35% yield) of thetitle compound. MS(ESI+) m/z 277 (M+H)+

Intermediate 901-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(5-methylthiophen-2-yl)urea

In a microwave vial, previously equipped magnetic stirrer, was added5-methylthiophene-2-carboxylic acid (0.30 g, 0.0021 mol) and Toluene (10ml). This solution was cooled to 0° C. and triethylamine (0.59 ml,0.0042 mol) was added drop wise. Diphenyl phosphoryl azide (DPPA, 0.63g, 0.0023 mol) was added drop wise to the resulting mixture and stirredat 0° C. for 1 h. 3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43,0.32 g, 0.0012 mol) was added drop wise in Toluene (8 ml). The resultingreaction mixture was stirred at 110° C. for 16 h. The solvent wasevaporated, and the reaction mixture was quenched with water (40 ml).The product was extracted with Ethyl acetate (3×50 ml). The combinedorganic layer was washed with brine (40 ml) and dried over sodiumsulphate and the solvent evaporated under reduced pressure. The crudeproduct was purified by Combi-flash chromatography using 30% ethylacetate in hexanes as an eluent to obtain 0.32 g of the title compound.¹H NMR (400 MHz, DMSO-d6) δ ppm 9.41 (s, 1H), 8.71 (s, 1H), 7.38 (s,1H), 7.29 (t, J=7.6 Hz, 2H), 7.02-6.95 (m, 3H), 6.83 (d, J=7.6, 2H),6.48 (d, J=2.4 Hz, 1H), 6.35 (d, J=3.6 Hz, 1H), 4.04 (t, J=4.4 Hz, 2H),3.49 (t, J=4.8 Hz, 2H), 3.15 (s, 3H), 2.33 (s, 3H). MS(ESI+) m/z 399(M+H)+

Intermediate 91 1,3-bis(3-methyl-4-phenoxyphenyl)urea

In a RBF previously equipped with a magnetic stirrer was added3-methyl-4-phenoxyaniline (commercially available, 0.3 g, 0.0015 mol),NaHCO₃ (0.75 g, 0.009 mol) and DCM (6 ml). The mixture was cooled to 0°C., and triphosgene (0.589 g, 0.0019 mol) was added and reaction mixturewas stirred for 4 h. 3-methyl-4-phenoxyaniline (commercially available,0.3 g, 0.0015 mol) and NaHCO₃(0.75 g, 0.009 mol) were added. Theresulting reaction mixture was stirred at 25° C. for 16 h. The solventwas evaporated and the reaction mixture was quenched with water (30 ml)and product was extracted with EtOAc (3×40 ml). The combined organiclayer was washed with brine (30 ml) and the organic layer was dried oversodium sulphate and the solvent evaporated under reduced pressure toobtain crude product. The crude product was purified by Combi-flashchromatography using 20% ethyl acetate in hexanes as an eluent to yield0.30 g (46% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δppm 8.68 (s, 2H), 7.44 (d, J=2.0 Hz, 2H), 7.38-7.26 (m, 6H), 7.04 (t,J=7.2 Hz, 2H), 6.93-6.81 (m, 6H), 2.12 (s, 6H). MS (ES+) m/z 425 [M+H]⁺

Intermediate 92 Phenyl (3-methyl-4-phenoxyphenyl)carbamate

In a RBF previously equipped with a magnetic stirrer was added3-methyl-4-phenoxyaniline (commercially available, 1.00 g, 0.005 mol) inDCM (10 ml) and the mixture was cooled to 0° C. Triethylamine (1.41 ml,0.010 mol) was added and then phenyl chloroformate (0.67 ml, 0.0055 mol)was added drop wise. The reaction mixture was allowed to reach roomtemperature and stirred at 25° C. for 2 h. The reaction mixture wasquenched with water (50 ml) and product was extracted with DCM (3×50ml). The combined organic layer was washed with brine (50 ml) dried oversodium sulphate and the solvent evaporated under reduced pressure. Thecrude product was purified by Combi-flash chromatography using 30% ethylacetate in hexanes as an eluent to yield 1.0 g (62% yield) of the titlecompound. MS (ES+) m/z 320 [M+H]⁺

Intermediate 931-(3-methyl-4-phenoxyphenyl)-3-(1-phenyl-1H-pyrazol-4-yl)urea

In a RBF previously equipped with a magnetic stirrer phenyl(3-methyl-4-phenoxyphenyl)carbamate (Intermediate 92, 1.0 g, 0.0031 mol)in DMF (7 ml) was added and the mixture cooled to 0° C. Triethylamine(0.88 ml, 0.0063 mol) was added drop wise followed drop-wise addition of1-Phenyl-1H-pyrazol-4-ylamine (0.335 g, 0.0031 mol) in DMF (3 ml). Theresulting reaction mixture was allowed to reach room temperature andstirred at 90° C. for 16 h. The reaction mixture was allowed cool atroom temperature and n-hexane was added. The solid product precipitatedand filtered through Buchner funnel to get crude product. The crudeproduct was purified by Combi-flash chromatography using 30% ethylacetate in hexanes as an eluent to yield 0.23 g (19% yield of the titlecompound. MS (ES+) m/z 385 [M+H]⁺

Intermediate 94 1-(3-bromo-4-phenoxyphenyl)-3-phenylurea

In a RBF previously equipped with a magnetic stirrer3-bromo-4-phenoxyaniline (commercially available, 1.00 g, 0.0038 mol)and DCM (10 ml) was added. Triethylamine (1.06 ml, 0.0076 mol) was addedat 0° C. followed by the addition of phenyl isocyanate (0.45 g, 0.0038mol). The reaction mixture was allowed to reach 25° C. and stirred for 2h. The obtained solid precipitates were filtered out and washed withn-pentane (15 ml) to yield 0.90 (62% yield) of the title compound. ¹HNMR (400 MHz, DMSO-d6) δ ppm 8.91 (s, 1H), 8.78 (s, 1H), 8.02 (d, J=2.4Hz, 1H), 7.48 (app d, 2H), 7.39-7.28 (m, 5H), 7.11-7.07 (m, 2H), 7.00(t, J=7.2 Hz, 1H), 6.90 (app d, 2H). MS(ESI+) m/z 383 (M+H)⁺

Intermediate 95 1-(2-methyl-4-phenoxyphenyl)-3-phenylurea

In a RBF previously equipped with a magnetic stirrer was added2-methyl-4-phenoxyaniline (commercially available, 0.35 g, 0.0017 mol)and triethylamine (0.49 ml, 0.0035 ml) in DCM (3.5 ml) and the mixturewas cooled to 0° C. Phenyl isocyanate (0.20 g, 0.0017 mol) was added andthe reaction mixture was allowed to reach 25° C. and stirred for 3 h.The solid product was filtered off and washed with n-pentane and driedunder vacuum to yield 0.370 g (66% yield) of the title compound.MS(ESI+) m/z 319 (M+H)+

Intermediate 96 Phenyl (2-methyl-4-phenoxyphenyl)carbamate

In a RBF previously equipped with a magnetic stirrer was taken2-methyl-4-phenoxyaniline (commercially available, 0.90 g, 0.0045 mol)in DCM (9.0 ml) and the mixture was cooled to 0° C. Triethylamine (1.90ml, 0.0135 mol) was added followed by drop wise addition of phenylchloroformate (1.65 ml, 0.0135 mol). The reaction mixture was allowed toreach 25° C. and stirred for 2 h. The reaction mixture was quenched withwater (50 ml) and the product was extracted with DCM (3×50 m). Thecombined organic layer was washed with brine (50 ml). The organic layerwas dried over sodium sulphate and the solvent removed under reducedpressure to obtain 2.0 g crude title compound that was used in nextstep. MS(ESI+) m/z 320(M+H)+

Intermediate 97 1-(2-methyl-4-phenoxyphenyl)-3-(4-methylphenyl)urea

In a RBF previously equipped with a magnetic stirrer was taken phenyl(2-methyl-4-phenoxyphenyl)carbamate (Intermediate 96, 1.00 g, 0.0031mol) in DMF (7 ml) and the mixture was cooled to 0° C. Triethylamine(0.88 ml, 0.0063 mol) was added drop wise followed by 4-methyl-aniline(0.335 g, 0.0031 mol) in DMF (8 ml). The reaction mixture allowed toreach room temperature and then stirred at 100° C. for 16 h. Thereaction mixture was allowed to cool to room temperature and n-hexanewas added. The solid product precipitated and was filtered throughBuchner funnel to get 0.50 g crude title compound that was used in nextstep without further purification. MS(ESI+) m/z 320 (M+H)⁺

Intermediate 98 1-(1-benzofuran-4-yl)-3-(3-methyl-4-phenoxyphenyl)urea

In a RBF previously equipped with a magnetic stirrer was added phenyl(3-methyl-4-phenoxyphenyl)carbamate (Intermediate 92, 0.50 g, 0.00156mol) in DMF (3 ml) and the mixture was cooled to 0° C. Triethylamine(0.44 ml, 0.00313 mol) was added drop wise and followed by drop wiseaddition of 4-amino-benzofuran (0.208 g, 0.00156 mol) in DMF (2 ml). Thereaction mixture was stirred at 100° C. for 16 h. The reaction mixturewas allowed cool at room temperature and n-hexane was added and stirredfor 5 min. The obtained solid was collected by filtration to yield 0.25g of crude title compound that was used in the next step without furtherpurification. MS(ESI+) m/z 359 (M+H)⁺

Intermediate 99 1-(1-benzofuran-7-yl)-3-(3-methyl-4-phenoxyphenyl)urea

In a RBF previously equipped with a magnetic stirrer was taken phenyl(3-methyl-4-phenoxyphenyl)carbamate (Intermediate 92, 1.0 g, 0.00313mol) in DMF (7 ml) and the mixture was cooled to 0° C. Triethylamine(0.88 ml, 0.0063 mol) was added followed by drop wise addition of7-amino-benzofuran (0.417, 0.00313 mol) in DMF (3 ml). The reactionmixture was stirred at 100° C. for 16 h. The reaction mixture wasallowed to cool to room temperature and n-hexanes was added. Afterstirring for 5 min the obtained solid was collected by filtration toyield 0.60 g of the crude title compound that was used without furtherpurification in the next step. MS(ESI+) m/z 359 (M+H)⁺

Intermediate 100 2-(2-fluoro-5-nitrophenyl)-N,N-dimethylacetamide

2-Fluoro-5-nitrophenyl)acetic acid (commercially available, 3.0 g, 15mmol), dimethyl amine (10% in THF, 10.1 g, 22.6 mmol) and HATU (11.45 g,30.1 mmol) in DMF (30 ml) was added to a RBF previously equipped with amagnetic stirrer and nitrogen balloon and the mixture was cooled to 0°C. After 30 minutes, N,N-Diisopropylethylamine (5.20 ml) was added dropwise and the reaction mixture was stirred at room temperature for 3 h.The reaction mixture was quenched with water (150 ml). The product wasextracted with ethyl acetate (3×100 ml) and the combined organic layerwas washed with brine (100 ml). The organic layer was dried over sodiumsulphate and the solvent evaporated under reduced pressure. The crudeproduct was purified by combi flash chromatography using 2% Methanol inDCM as an eluent to obtain 3.6 g of the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 8.27-8.20 (m, 2H), 7.48 (t, J=9.0 Hz, 1H), 3.92 (s, 2H), 3.10(s, 3H), 2.87 (s, 3H); MS (ES+) m/z 227 [M+H]⁺

Intermediate 101 N,N-dimethyl-2-(5-nitro-2-phenoxyphenyl)acetamide

Phenol (1.79 g, 19.0 mmol) and NMP (20 ml) was added to a RBF previouslyequipped with a magnetic stirrer and nitrogen balloon, and K₂CO₃ (6.60g, 47.7 mmol) was added at RT. After stirring for 1 h,2-(2-fluoro-5-nitrophenyl)-N,N-dimethylacetamide (Intermediate 90, 3.6g, 15.9 mmol) in NMP (16 ml) was added to mixture and the reactionmixture was stirred at RT for 16 h. The reaction mixture was quenchedwith water (150 ml) and extracted with Ethyl acetate (3×100 ml). Thecombined organic layer was washed with brine (100 ml). The organic layerwas dried over sodium sulphate and the solvent removed under reducedpressure. The crude product was purified by combi flash chromatographyusing 30% Ethyl acetate in hexane as an eluent to obtain 3.6 g (75%yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆): δ 8.24 (d,J=2.4 Hz, 1H), 8.12 (dd, J=9.2, 2.8 Hz, 1H), 7.49 (t, J=7.6 Hz, 2H),7.29 (t, J=7.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 2H), 6.83 (d, J=9.2 Hz, 1H),3.92 (s, 2H), 3.07 (s, 3H), 2.85 (s, 3H); MS (ES+) m/z 301 [M+H]⁺

Intermediate 102 2-(5-amino-2-phenoxyphenyl)-N,N-dimethylacetamide

N,N-Dimethyl-2-(5-nitro-2-phenoxyphenyl)acetamide (Intermediate 101,3.50 g, 11.6 mmol) in Methanol (70 ml) was added to a RBF previouslyequipped with a magnetic stirrer and nitrogen balloon. 10% Pd/C (50%wet, 0.35 g) was added to the stirred solution under N₂ atmosphere. Thereaction mixture was stirred for 1 hours under H₂ (gas). The reactionmixture was filtered through a celite bed, washed with methanol and thesolvent was removed under reduced pressure to obtain 3.2 g of the titlecompound. ¹H NMR (400 MHz, DMSO-d₆): δ 7.34-7.24 (m, 2H), 6.99 (t, J=7.2Hz, 1H), 6.82 (d, J=7.6 Hz, 2H), 6.67 (d, J=8.0 Hz, 1H), 6.50-6.46 (m,2H), 5.01 (s, 2H), 3.40 (s, 2H), 2.87 (s, 3H), 2.75 (s, 3H); MS (ES+)m/z 271 [M+H]⁺

Intermediate 1031-(Dimethylamino)-2-[2-phenoxy-5-(3-phenylureido)phenyl]-1-ethanone

2-(5-Amino-2-phenoxyphenyl)-N,N-dimethylacetamide (Intermediate 102,1.00 g, 3.6 mmol) and triethylamine (0.50 ml, 3.6 mmol) in DCM (10 ml)was added to a RBF previously equipped with a magnetic stirrer andnitrogen balloon, and the mixture was cooled to 0° C. Phenyl isocyanate(0.44 g, 3.6 mmol) was added, and the reaction mixture was allowed toreach 25° C. and stirred for 3 h. The reaction mixture was quenched withwater (50 ml) and extracted with ethyl acetate (3×50 ml). The combinedorganic layer was washed with brine (50 ml). The organic layer was driedover sodium sulphate and the solvent removed under reduced pressure toobtain 0.80 g (55% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d₆): δ 8.69 (s, 1H), 8.61 (s, 1H), 7.45 (d, J=8.0 Hz, 2H),7.41-7.26 (m, 6H), 7.06 (t, J=7.0 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 6.90(d, J=7.6 Hz, 2H), 6.85 (d, J=9.2 Hz, 1H), 3.59 (s, 2H), 2.93 (s, 3H),2.77 (s, 3H); MS (ES+) m/z 388 [M+H]⁺

Intermediate 104 2-(2-fluoro-5-nitrophenoxy)-N,N-dimethylacetamide

2-Fluoro-5-nitrophenol (commercially available, 5.00 g, 31.8 mmol) inacetonitrile (30 ml) was added to a RBF previously equipped with amagnetic stirrer and nitrogen balloon. K₂CO₃ (13.19 g, 95.4 mmol) wasadded at room temperature. After 15 min, 2-chloro-N,N-dimethylacetamide(3.87 g, 31.8 mmol) in acetonitrile (20 ml) was added to the mixture andthe reaction mixture was heated at 80° C. for 16 h. The reaction mixturewas filtered through celite bed, the bed washed with acetonitrile andthe solvent was removed under reduced pressure to obtain 6.10 g (79%yield) the title compound which used in next step without any furtherpurification. MS (ES+) m/z 243 [M+H]⁺

Intermediate 105 N,N-dimethyl-2-(5-nitro-2-phenoxyphenoxy)acetamide

Phenol (2.84 g, 30.2 mmol) in NMP (41 ml) and K₂CO₃ (13.91 g, 100 mmol)was added to a RBF previously equipped with a magnetic stirrer andnitrogen balloon, and stirred at room temperature. After 1 h,2-(2-fluoro-5-nitrophenoxy)-N,N-dimethylacetamide (Intermediate 104,6.10 g, 25.1 mmol) in NMP (20 ml) was added and the reaction mixture washeated at 85° C. for 16 h. The reaction mixture was quenched with water(150 ml) and extracted with Ethyl acetate (3×100 ml). The combinedorganic layer was washed with brine (100 ml). The organic layer wasdried over sodium sulphate and the solvent removed under reducedpressure to obtain 7.20 g (90% yield) of the title compound that used innext step without any further purification. MS (ES+) m/z 317 [M+H]⁺

Intermediate 106 2-(5-amino-2-phenoxyphenoxy)-N,N-dimethylacetamide

N,N-Dimethyl-2-(5-nitro-2-phenoxyphenoxy)acetamide (Intermediate 105,7.20 g, 22.7 mmol) in methanol (72 ml) was added to a RBF previouslyequipped with a magnetic stirrer and nitrogen balloon. 10% Pd/C (50%wet, 0.72 g) was added to the stirred mixture under N₂ atmosphere. Thereaction mixture was stirred for 2 hours under H₂ (gas). The reactionmixture was filtered through a celite bed, the bed was washed withmethanol and the solvent was removed under reduced pressure to obtain3.0 g (46% yield) of the title compound. MS (ES+) m/z 287 [M+H]⁺

Intermediate 1071-(Dimethylamino)-2-[2-phenoxy-5-(3-phenylureido)phenoxy]-1-ethanone

2-(5-amino-2-phenoxyphenoxy)-N,N-dimethylacetamide (Intermediate 106,1.50 g, 5.2 mmol) and triethylamine (0.73 ml, 5.2 mmol) in DCM (15 ml)was added to a RBF previously equipped with a magnetic stirrer andnitrogen balloon, and stirred at 0° C. Phenyl isocyanate (0.62 g, 5.2mmol) was added and the reaction mixture was allowed to reach 25° C. andstirred for 3 h. The reaction mixture was quenched with water (30 ml)and product was extracted with DCM (3×50 m). The combined organic layerwas washed with brine (30 ml) and dried over sodium sulphate. Thesolvent was removed under reduced pressure. The crude product waspurified by combi flash chromatography using 80% ethyl acetate inhexanes as an eluent to yield 0.720 g (33% yield) of the title compound.MS (ES+) m/z 406 [M+H]⁺

Intermediate 108 3-Methyl-2-phenoxy-5-(phenoxycarbonylamino)pyridine

In a RBF previously equipped with a magnetic stirrer was taken5-Methyl-6-phenoxy-3-pyridylamine (commercially available, 0.5 g, 0.0025mol) in DCM and the mixture was cooled to 0° C. TEA (0.35 ml, 0.0025mol) was added followed by drop wise addition of Phenyl Chloroformate(0.39 ml, 0.0025 mol). The reaction mixture was allowed to reach 25° C.and stirred for 2 h. The reaction mixture was quenched with water (50ml) and both the layers were separated. The aqueous layer was extractedwith DCM (2×50 ml). The combined organic layer was washed with brine (50ml), dried over sodium sulphate and the solvent removed under reducedpressure to obtain crude product. The crude product was purified byCombi-flash chromatography using 15% ethyl acetate in hexanes as aneluent to yield 0.5 g (62% yield) of the title compound. MS (ES+) m/z321 [M−H]+.

Intermediate 109 3-(5-Methyl-6-phenoxy-3-pyridyl)-1-(4-methylphenyl)urea

In a RBF previously equipped with a magnetic stirrer was taken3-Methyl-2-phenoxy-5-(phenoxycarbonylamino)pyridine (Intermediate 108,0.5 g, 0.0015 mol) in DMF (2 ml) and the mixture was cooled to 0° C. Tothe reaction mixture TEA (0.21 ml, 0.0031 mol) was added followed bydrop wise addition of 4-methyl-aniline (0.16 g, 0.0015 mol) in DMF (3ml. The reaction mixture was allowed to reach room temperature and thenheated to 100° C. and stirred for 2 h. The reaction mixture was quenchedwith water (50 ml) and product was extracted with DCM (3×30 ml). Thecombined organic layer was washed with brine (25 ml), dried over sodiumsulphate and the solvent removed under reduced pressure to obtain 0.30 g(57% yield) of the title compound which was used in the next stepwithout further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.66 (s, 2H),7.99 (s, 1H), 7.91 (s, 1H), 7.40-7.33 (m, 4H), 7.15 (t, J=7.2 Hz, 1H),7.10 (app d, 2H), 7.05 (app d, 2H), 2.28 (s, 3H), 2.25 (s, 3H). MS (ES+)m/z 334 [M−H]+.

EXAMPLES Example 11-(4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a microwave tube 1-(4-phenoxyphenyl)-3-phenylurea (Intermediate 1,0.110 g, 0.00082 mol) and ethoxycarbonyl isocyanate (0.042 g, 0.00036mol) were taken in bromo benzene (1.10 mL) and heated in a microwavereactor at 150° C. for 1 h. The reaction mixture was diluted with water(50 ml) and extracted with ethyl acetate (3×40 ml). The combine organiclayers were washed with brine (30 ml), dried over sodium sulfate andevaporated under reduced pressure to obtain a crude product. The crudeproduct was purified by combi flash chromatography using 0-100% ethylacetate in hexanes as a mobile phase and 60-120 silica as stationaryphase. The obtained product was further purified using 5 mM ammoniaacetate as a modifier and water:Acetonitrile (0-100% gradient system) asa mobile phase using prep HPLC purification to obtain 0.033 g (24%yield) of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.07-7.12(m, 4H) 7.19 (br. t, 1H) 7.31 (m, 2H) 7.34-7.42 (m, 4H) 7.47-7.56 (m,3H) 8.24 (s, 1H); MS (ES−) m/z 372 [M−H]⁻

Example 21-(4-methoxyphenyl)-3-(4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

Ethoxycarbonyl isocyanate (0.103 g, 0.00089 mol) was added to a solutionof 1-(4-methoxyphenyl)-3-(4-phenoxyphenyl)urea (Intermediate 2, 0.200 g,0.00059 mol) under stirring in toluene (2.0 mL) at 0° C. The reactionmixture was stirred at 110° C. for 16.0 hrs in a sealed tube. Thereaction mixture was quenched with ice-water (30 ml) and extracted withEthyl Acetate (3×30 ml). The combined organic layers were washed withbrine (30 ml). The organic layer was dried over sodium sulfate andevaporated under reduced pressure to obtain crude product. The crudeproduct was purified by preparative HPLC using 0.1% ammonia as amodifier and water:Acetonitrile (0-100% gradient system) as a mobilephase to yield 0.018 g (9% yield) of the title compound. ¹H NMR (400MHz, DMSO-d6) δ ppm 3.79 (s, 3H) 6.98-7.12 (m, 6H) 7.17-7.23 (m, 1H)7.26-7.31 (m, 2H) 7.34-7.39 (m, 2H) 7.42-7.48 (m, 2H) 11.92 (s, 1H); MS(ES+) m/z 404 [M+H]⁺

Example 33-[2,4,6-trioxo-3-(4-phenoxyphenyl)-1,3,5-triazinan-1-yl]benzonitrile

Ethoxycarbonyl isocyanate (0.083 g, 0.00072 mol) was added to a solutionof (Intermediate 3, 0.160 g, 0.00048 mol) in toluene (1.60 mL) at 0° C.The reaction mixture was stirred at 110° C. for 16 h in a sealed tube.The reaction mixture was quenched with ice-water (50 ml) and product wasextracted with Ethyl Acetate (3×40 ml). The combined organic layers werewashed with brine (30 ml), dried over sodium sulfate and evaporatedunder reduce pressure to obtain crude product. The crude product waspurified on column chromatography by 70% ethyl acetate in hexane as amobile phase and 60-120 silica as stationary phase. The obtained productwas further purified on preparative HPLC using 5 mM ammonium acetate asa modifier and water:Acetonitrile (0-100% gradient system) as a mobilephase to yield 0.020 g (10% yield) of the title compound. ¹H NMR (400MHz, DMSO-d6) δ ppm 7.04-7.12 (m, 4H) 7.18-7.24 (m, 1H) 7.33-7.38 (m,2H) 7.42-7.48 (m, 2H) 7.60-7.80 (m, 2H) 7.89-8.01 (m, 2H) 12.18 (s, 1H);MS (ES−) m/z 397 [M−H]−

Example 41-(3-methoxyphenyl)-3-(4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

Ethoxycarbonyl isocyanate (0.077 g, 0.00044 mol) was added to thesolution of 1-(3-methoxyphenyl)-3-(4-phenoxyphenyl)urea (Intermediate 4,0.150 g, 0.00029 mol) in toluene (1.5 mL) at 0° C. The reaction mixturewas stirred at 110° C. for 16 h in a sealed tube. The reaction mixturewas quenched with ice-water (50 ml) and extracted with ethyl acetate(3×40 ml). The combined organic layers were washed with brine (30 ml),dried over sodium sulfate and evaporated under reduced pressure toobtain a crude product. The crude product was purified by ethyl acetateas a mobile phase and 60-120 silica as stationary phase on columnchromatography. The obtained product was further purified usingpreparative HPLC purification using 5 mM ammonium acetate as a modifierand water:Acetonitrile (0-100% gradient system) as a mobile phase toyield 0.012 g (6.7% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d6) δ ppm 3.77 (s, 3H) 6.93-7.03 (m, 3H) 7.04-7.12 (m, 4H)7.17-7.24 (m, 1H) 7.34-7.48 (m, 5H) 11.99 (s, 1H); MS (ES+) m/z 404[M+H]⁺

Example 51-(3-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

Ethoxycarbonyl isocyanate (0.108 g, 0.00094 mol) was added to thesolution of 1-(3-methyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 5,0.200 g, 0.00062 mol) in Toluene (2.0 mL) at 0° C. The resultingreaction mixture was stirred at 110° C. for 16 h in a microwave vial.Reaction mixture was quenched with ice-water (50 ml) and extracted withEthyl Acetate (3×40 ml). The combine organic layers were washed withbrine (30 ml). The organic layer was dried over sodium sulfate andevaporated under reduced pressure to obtain crude product. The crudeproduct was purified on combi flash chromatography using 30% ethylacetate in hexane as a mobile phase and 60-120 silica as stationaryphase. The obtained product was further purified using preparative HPLCpurification using 5 mM ammonium acetate as a modifier andwater:acetonitrile (0-100% gradient system) as a mobile phase to yield0.050 g (20% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δppm 2.20 (s, 3H) 6.88-7.01 (m, 3H) 7.11-7.24 (m, 2H) 7.30-7.53 (m, 8H)12.02 (s, 1H); MS (ES+) m/z 388 [M+H]⁺

Example 6 1-[4-(benzyloxy)phenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.181 g, 0.0015 mol) was added to a solutionof 1-[4-(benzyloxy)phenyl]-3-phenylurea (Intermediate 7, 0.250 g,0.0007) in toluene (2.5 mL) at 0° C. The reaction mixture was allowed tocome to 25° C. and then heated at 110° C. for 16 h. The reaction mixturewas quenched with ice-water (50 ml) and product extracted with ethylacetate (3×40 ml). The combined organic layers washed with brine (30ml), dried over sodium sulfate and evaporated under reduce pressure toobtain crude product. The crude product was purified on silica gel(60-120 mesh) using 30% ethyl acetate in hexane as an eluent to obtained0.030 g (10% yield) the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm5.14 (s, 2H) 7.04-7.12 (m, 2H) 7.26-7.52 (m, 12H) 11.97 (s, 1H); MS(ES−) m/z 386 [M−H]⁻

Example 71-[4-(4-chlorophenoxy)phenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrerethoxycarbonyl isocyanate (0.135 g, 0.00110 mol) was added to a solutionof 1-[4-(4-chlorophenoxy)phenyl]-3-phenylurea (Intermediate 8, 0.265 g,0.00078) in toluene (2.60 mL) at 0° C. The reaction mixture was allowedto come at 25° C. and heated at 110° C. for 16 h. The reaction mixturewas quenched with NaHCO₃ (50 ml) and product extracted with ethylacetate (3×40 ml). The combine organic layers were washed with brine (30ml), dried over sodium sulfate and evaporated under reduced pressure toobtain crude product. The crude product was purified on silica gel(60-120 mesh) using 40% ethyl acetate in hexane as an eluent to yield0.010 g (3% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δppm 7.07 (m, 4H) 7.35-7.52 (m, 9H) 12.02 (s, 1H); MS (ES−) m/z 406[M−H]−

Example 84-[4-(2,4,6-trioxo-3-phenyl-1,3,5-triazinan-1-yl)phenoxy]benzonitrile

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.130 g, 0.0011 mol) was added to thesolution of 1-[4-(4-cyanophenoxy)phenyl]-3-phenylurea (Intermediate 10,0.250 g, 0.00076 mol) in toluene (3.00 mL) at 0° C. The reaction mixturewas stirred at 110° C. for 16 h. The solvent was evaporated underreduced pressure to obtain crude product. The crude product was purifiedby 0-30% Ethyl acetate in Hexane as a mobile phase and 60-120 silica asstationary phase on Combi flash chromatography. The obtained materialwas further purified by preparative HPLC purification using 0.1% ammoniain water and acetonitrile as mobile phases ((0-100% gradient system) toyield 0.007 g (2% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d6) δ ppm 7.14-7.27 (m, 4H) 7.36-7.40 (m, 2H) 7.42-7.52 (m, 5H)7.87-7.93 (m, 2H) 12.06 (s, 1H); MS (ES−) m/z 397 [M−H]⁻

Example 91-(2-methoxy-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

1-(2-methoxy-4-phenoxyphenyl)-3-phenylurea (Intermediate 11, 0.300 g,0.00089 mol) in dry toluene (3.00 mL) was added to a seal tubepreviously equipped with a magnetic stirrer and cooled to 0° C.Ethoxycarbonyl isocynate (0.100 g, 0.00089 mol) was added and thereaction mixture was stirred at 110° C. for 16 h. The reaction mixturewas quenched with ice-water (20 ml) and product extracted with ethylacetate (3×20 ml). The combined organic layers were washed with brine(30 ml). and dried over sodium sulfate and evaporated under reducedpressure to obtain the crude product. The crude product was purified oncolumn chromatography using 35% ethyl acetate in hexane as a mobilephase and 60-120 silica to yield 0.015 g (4% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H) 6.50-6.58 (m, 1H)6.85-6.89 (m, 1H) 7.08-7.15 (m, 2H) 7.18-7.24 (m, 1H) 7.29-7.34 (m, 1H)7.35-7.40 (m, 2H) 7.41-7.52 (5H) 12.09 (s, 1H); MS (ES−) m/z 402 [M−H]⁻

Example 101-[4-(morpholin-4-yl)phenyl]-3-(4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

Ethoxycarbonyl isocyanate (0.038 g, 0.00033 mol) was added to a solutionof 1-(4-Morpholinophenyl)-3-(4-phenoxyphenyl)urea (Intermediate 12,0.130 g, 0.00033 mol)) in dry toluene (1.30 ml) at 0° C. in a 30 ml sealtube previously equipped with a magnetic stirrer. The reaction mixturewas allowed to come to 25° C. and then heated at 110° C. for 16 h. Thereaction mixture was quenched with ice-water (50 ml) and extracted withethyl acetate (3×40 ml). The combined organic layers were washed withbrine (30 ml), dried over sodium sulfate and evaporated under reducedpressure to obtain the crude product. The crude product was purified onsilica gel (100-200 mesh) using 80% ethyl acetate in hexane as an eluentto yield 0.010 g (6.5% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d6) δ ppm 3.13-3.18 (m, 4H) 3.72-3.78 (m, 4H)6.97-7.02 (m, 2H) 7.03-7.13 (m, 4H) 7.17-7.24 (m, 3H) 7.34-7.40 (m, 2H)7.41-7.49 (m, 2H) 11.92 (s, 1H); MS (ES+) m/z 459 [M+H]⁺

Example 111-(3-methoxy-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

Ethoxycarbonyl isocyanate was added (0.103 g, 0.0008 mol) to thesolution of 1-(3-methoxy-4-phenoxyphenyl)-3-phenylurea (Intermediate 13,0.200 g, 0.0005 mol) in toluene (2.00 mL) at 0° C. in a 30 ml seal tubepreviously equipped with a magnetic stirrer. The reaction mixture wasstirred and allowed to reach 25° C. and then heated at 110° C. for 16 h.The reaction mixture was quenched with water (50 ml) and extracted withethyl acetate (3×40 ml). The combined organic layers were washed withbrine (30 ml), dried over sodium sulfate and evaporated under reducedpressure to obtain the crude product. The crude product was purified onsilica gel (60-120 mesh) using 60% ethyl acetate in hexane as an eluent.The compound was recrystallized in dichloromethane/hexane to yield 0.045g (18% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm3.72 (s, 3H) 6.86-6.92 (m, 2H) 6.97-7.03 (m, 1H) 7.05-7.12 (m, 2H)7.24-7.27 (m, 1H) 7.32-7.41 (m, 4H) 7.42-7.53 (m, 3H) 12.06 (s, 1H); MS(ES−) m/z 402 [M−H]−

Example 122-phenoxy-5-(2,4,6-trioxo-3-phenyl-1,3,5-triazinan-1-yl)benzonitrile

Ethoxycarbonyl isocyanate (0.140 g, 0.00110 mol) was added to1-(3-cyano-4-phenoxyphenyl)-3-phenylurea (Intermediate 14, 0.250 g,0.00075 mol) in dry toluene (2.5 mL) at 0° C. in a 30 ml seal tubepreviously equipped with a magnetic stirrer. The reaction mixture wasstirred at 110° C. for 16 h. The solvent was evaporated under reducedpressure to obtain the crude product. The crude product was purified byusing 0.1% TFA in water and acetonitrile as a mobile phase (0-100%gradient system) in preparative HPLC purification to yield 0.034 g (11%yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.00 (d,1H) 7.23-7.29 (m, 2H) 7.31-7.39 (m, 3H) 7.40-7.78 (m, 5H) 7.69 (dd, 1H)7.95 (d, 1H) 12.16 (s, 1H); MS (ES−) m/z 397 [M−H]⁻

Example 131-(2-methoxy-5-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

1-(2-methoxy-5-methyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 17,0.260 g, 0.00074 mol) was dissolved in dry toluene (2.60 mL) in a sealtube and cooled to 0° C. Ethoxycarbonyl isocyanate (0.094 g, 0.00082mol) was added and the reaction mixture was stirred at 110° C. for 16 h.The solvent was evaporated under reduced pressure to obtain a crudeproduct. The crude product was purified on Combi flash chromatography byusing ethyl acetate as a mobile phase and 60-120 silica as stationaryphase. The obtained product was further purified by using 10 mM ammoniumbicarbonate as modifier and water:acetonitrile (0-100% gradient system)as a mobile phase in preparative HPLC purification to yield 0.042 g (13%yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s,3H) 3.67 (s, 3H) 6.72 (s, 1H) 6.91-6.97 (m, 2H) 7.07-7.14 (m, 1H) 7.28(s, 1H) 7.33-7.51 (m, 7H) 12.06 (s, 1H); MS (ES+) m/z 418 [M+H]⁺

Example 141-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a 10 ml seal tube previously equipped with a magnetic stirrer andnitrogen balloon, ethoxycarbonyl isocyanate (0.033 g, 0.00030 mol) wasadded drop wise to the solution of1-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 20,0.090 g, 0.00025 mol) in dry toluene (0.9 mL) at 25° C. The reactionmixture was heated at 110° C. for 16 h. The reaction mixture wasconcentrated under reduced pressure to obtain a crude product. The crudeproduct was purified by preparative HPLC with 5 mM ammonium acetate inwater:acetonitrile as mobile phase (0-100% gradient system) to yield0.008 g (8% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6 δ ppm2.10 (s, 3H) 3.67 (s, 3H) 6.72-6.77 (m, 2H) 6.93-6.96 (m, 1H) 6.97-7.03(m, 1H) 7.08-7.12 (m, 1H) 7.26-7.33 (m, 2H) 7.36-7.53 (m, 5H) 12.04 (s,1H); MS (ES−) m/z 416 [M−H]−

Example 151-[3-(cyclopentyloxy)-4-phenoxyphenyl]-3-methyl-1,3,5-triazinane-2,4,6-trione

1-[3-(cyclopentyloxy)-4-phenoxyphenyl]-3-methylurea (Intermediate 23,0.180 g, 0.0005516 mol) was dissolved in toluene (1.80 mL) in a 30 mlseal tube previously equipped with a magnetic stirrer and cooled to 0°C. Ethoxycarbonyl isocyanate (0.069 g, 0.0006067 mol) was added and thereaction mixture was stirred at 110° C. for 16 h. The solvent wasevaporated under reduced pressure to obtain the crude product. The crudeproduct was purified on combi flash chromatography by using a 0-100%ethyl acetate gradient in hexane as a mobile phase and 60-120 silica asstationary phase. The product was further purified by prep HPLCpurification using 3 mM ammonium acetate in water acetonitrile as amobile phase (0-100% gradient system) to yield 0.049 g (22% yield) ofthe title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.30-1.48 (m, 4H)1.49-1.60 (m, 2H) 1.67-1.80 (m, 2H) 3.16 (s, 3H) 4.69 (m, 1H) 6.84-6.93(m, 3H) 7.02-7.08 (m, 1H) 7.10-7.18 (m, 2H) 7.30-7.37 (m, 2H) 11.84 (s,1H); MS (ES−) m/z 394 [M−H]−

Example 161-(3-ethoxy-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer andnitrogen balloon, Ethoxycarbonyl isocyanate (0.083 ml, 0.00072 mol) wasadded drop wise to a solution of1-(3-ethoxy-4-phenoxyphenyl)-3-phenylurea (Intermediate 24, 0.230 g,0.00066 mol) in dry toluene (2.3 mL) at 0° C. The reaction mixture wasallowed to reach to 25° C. and then heated at 120° C. for 12 h. Thesolvent was evaporated under reduced pressure to obtain the crudeproduct. The crude product was purified by using 0.1% ammonia as amodifier and water:acetonitrile (0-100% as a gradient system) as amobile phase in preparative HPLC purification to yield 0.0145 g (5%yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (t,3H) 3.99 (q, 2H) 6.88-6.93 (m, 2H) 6.94-6.99 (m, 1H) 7.04-7.11 (m, 2H)7.20-7.24 (m, 1H) 7.31-7.39 (m, 4H) 7.4.0-7.52 (m, 3H) 12.05 (s, 1H); MS(ES−) m/z 416 [M−H]⁻

Example 171-[3-(oxolan-3-yloxy-4-phenoxyphenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrerEthoxycarbonyl isocyanate (0.130 g, 0.0011 mol) was added to thesolution of 1-[4-Phenoxy-3-(tetrahydrofur-3-yloxy)phenyl]-3-phenylurea(Intermediate 27, 0.400 g, 0.0010 mol) in toluene (4 mL) at 0° C. Thereaction mixture was stirred at 110° C. for 16 h. The solvent wasevaporated under reduced pressure to obtain crude product. The crudeproduct was purified on combi flash chromatography using ethyl acetateas a mobile phase and 60-120 silica as stationary phase. The crudeproduct was further purified by prep HPLC purification using using 0.1%ammonia as a modifier and water:acetonitrile (0-100% gradient system) asa mobile phase to yield 0.028 g (7% yield) of the title compound. ¹H NMR(400 MHz, DMSO-d6) δ ppm 1.75-1.85 (m, 1H) 2.02-2.15 (m, 1H) 3.49-3.70(m, 3H) 3.79-3.85 (m, 1H) 4.88-4.95 (m, 1H) 6.88-6.94 (m, 2H) 6.99-7.04(m, 1H) 7.05-7.14 (m, 2H) 7.22-7.25 (m, 1H) 7.31-7.53 (m, 7H) 12.06 (s,1H); MS (ES−) m/z 458 [M−H]⁻

Example 181-(3-methyl-4-phenoxyphenyl)-3-(pyridin-2-yl)-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,1-(3-methyl-4-phenoxyphenyl)-3-pyridin-2-ylurea (Intermediate 28, 0.250g, 0.0007 mol) was dissolved in Bromo Benzene (2.5 mL) at 0° C. To themixture Ethoxycarbonyl isocyanate (0.099 g, 0.0008 mol) was added. Theresulting reaction mixture was stirred at 110° C. for 16 h. The solventwas evaporated under reduced pressure to obtain crude product. The crudeproduct was purified on combi flash chromatography by using 0-100% ethylacetate in hexane as a mobile phase and 60-120 silica as stationaryphase. The obtained product was further purified using 5 mM ammoniaacetate as a modifier and water:acetonitrile (0-100% gradient system) asa mobile phase using preparative HPLC purification to yield 0.036 g (12%yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s,3H) 6.91 (d, 1H) 6.95-7.00 (m, 2H) 7.14 (t, 1H) 7.23 (dd, 1H) 7.35 (d,1H) 7.37-7.43 (m, 2H) 7.49-7.57 (m 2H) 8.01 (dt, 1H) 8.57-8.62 (m, 1H)12.12 (s, 1H); MS (ES−) m/z 387 [M−H]⁻

Example 191-phenyl-3-(1-phenyl-1H-indazol-5-yl)-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrerEthoxycarbonyl isocyanate (0.053 g, 0.0004 mol) was added to a solutionof 1-phenyl-3-(1-phenyl-1H-indazol-5-yl)urea (Intermediate 29, 0.140 g,0.0004 mol) in Toluene (1.4 mL) at 0° C. The reaction mixture wasallowed to reach 25° C. and then heated at 110° C. for 16 h. The solventwas evaporated under reduced pressure to obtain the crude product. Thecrude product was purified by using 0.01% ammonia as a modifier andwater:acetonitrile (0-100% gradient system) as a mobile phase in prepHPLC purification to yield 0.007 g (4% yield) of the title compound. ¹HNMR (400 MHz, DMSO-d6) δ ppm 7.38-7.53 (m, 7H) 7.59-7.66 (m, 2H)7.78-7.83 (m, 2H) 7.90-7.95 (m, 2H) 8.47-8.49 (m, 1H) 12.05 (s, 1H); MS(ES−) m/z 396 [M−H]⁻

Example 201-phenyl-3-[4-(phenylamino)phenyl]-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.125 g, 0.0010 mol) was added to a solutionof 1-phenyl-3-[4-(phenylamino)phenyl]urea (commercially available, 0.300g, 0.0009 mol) in Bromobenzene (3.0 mL) at 0° C. The reaction mixturewas stirred in a microwave reactor at 150° C. for 3 h. The solvent wasevaporated under reduce pressure to obtain a crude product. The crudeproduct was purified on combi flash chromatography by using ethylacetate in hexane as a mobile phase and 60-120 silica as stationaryphase. The obtained product was further purified by using 3 mM ammoniaas modifier and water:acetonitrile (0-100% gradient system) as a mobilephase in preparative HPLC purification to yield 0.008 g (3% yield) ofthe title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.83-6.92 (m, 1H)7.05-7.57 (m, 13H) 8.34 (s, 1H) 11.94 (s, 1H); MS (ES+) m/z 373 [M+H]⁺

Example 211-(3-ethoxy-4-phenoxyphenyl)-3-methyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer andnitrogen balloon, ethoxycarbonyl isocyanate (0.083 mL, 0.00035 mol) wasadded drop wise to a solution of (Intermediate 30, 0.093 g, 0.00032 mol)in dry toluene (2.3 mL) at 0° C. The reaction mixture was allowed toreach 25° C. and then heated at 120° C. for 12 h. The solvent wasevaporated under reduced pressure to obtain a crude product. The crudeproduct was purified by preparative HPLC purification using 0.1% ammoniaas modifier and water:acetonitrile (0-100% gradient system) as a mobilephase to yield 0.026 g (22% yield) of the title compound. ¹H NMR (400MHz, DMSO-d6) δ ppm 1.18 (t, 3H) 3.16 (s, 3H) 3.97 (q, 2H) 6.88-6.95 (m,3H) 7.03-7.12 (m, 2H) 7.16-7.20 (m, 1H) 7.32-7.40 (m, 2H) 11.83 (s, 1H);MS (ES−) m/z 354 [M−H]−

Example 221-methyl-3-[3-(oxolan-3-yloxy)-4-phenoxyphenyl]-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,Ethoxycarbonyl isocyanate (0.042 g, 0.0003 mol) was added to a solutionof 1-methyl-3-[4-phenoxy-3-(tetrahydrofuran-3-yloxy)phenyl]urea(Intermediate 31, 0.110 g, 0.0003 mol) in Toluene (1.10 mL) at 0° C. Theresulting reaction mixture was heated at 110° C. for 16 h. The solventwas evaporated under reduced pressure to obtain crude product. The crudeproduct was purified on silica gel (60-120 mesh) using ethyl acetate asan eluent and re-purified by preparative HPLC purification using 0.1%formic acid in water acetonitrile as a mobile phase (0-100% gradientsystem) to yield 0.039 g (29% yield) of the title compound. ¹H NMR (400MHz, DMSO-d6) δ ppm 1.76-1.84 (m, 1H) 2.02-2.14 (m, 1H) 3.16 (s, 3H)3.49-3.70 (m, 3H) 3.78-3.85 (m, 1H) 4.85-4.91 (m, 1H) 6.88-6.98 (m, 3H)7.05-7.14 (m, 2H) 7.19 (d, 1H) 7.32-7.39 (m, 2H) 11.87 (s, 1H); MS (ES−)m/z 396 [M−H]⁻

Example 231-[3-(cyclopentyloxy)-4-phenoxyphenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.069 g, 0.0006 mol) was added to a solutionof 1-[3-(Cyclopentyloxy)-4-phenoxyphenyl]-3-phenylurea (Intermediate 32,0.180 g, 0.0005 mol) in bromobenzene (2.0 mL) at 0° C. The reactionmixture was stirred at 110° C. for 16 h. The solvent was evaporatedunder reduced pressure to obtain the crude product. The crude productwas purified on combi flash chromatography by using a 0-100% ethylacetate in hexane (gradient) as a mobile phase and 60-120 silica asstationary phase and further purified by using preparative HPLCpurification using 3 mM ammonia acetate in water:acetonitrile as amobile phase (0-100% gradient system) to yield 0.015 g (9% yield) of thetitle compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.48 (m, 4H)1.50-1.60 (m, 2H) 1.69-1.80 (m, 2H) 4.71 (s, 1H) 6.83-6.88 (m, 2H)6.94-6.98 (m, 1H) 7.02-7.07 (m, 1H) 7.11-7.15 (m, 1H) 7.18-7.21 (m, 1H)7.29-7.52 (m, 7H) 12.04 (s, 1H); MS (ES−) m/z 456 [M−H]⁻

Example 241-methyl-3-[3-(oxetan-3-ylmethoxy)-4-phenoxyphenyl]-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.042 g, 0.0003 mol) was added to a solutionof 1-methyl-3-[3-(oxetan-3-ylmethoxy)-4-phenoxyphenyl]urea (Intermediate36, 0.110 g, 0.0003 mol) in Toluene (1.10 mL) at 0° C. The reactionmixture was stirred at 110° C. for 16 h. The solvent was evaporatedunder reduced pressure to obtain the crude product. The crude productwas purified on combi flash chromatography by using 0-5% MeOH in DCM asa mobile phase and 60-120 silica as stationary phase. The product wasfurther purified by using 3 mM ammonia acetate as modifier andwater:acetonitrile (0-100% gradient system) as a mobile phase inpreparative HPLC purification to yield 0.006 g (4.5% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.13-3.23 (m, 1H) 3.16 (s, 3H)4.08-4.15 (m, 4H) 4.45-4.51 (m, 2H) 6.87-6.92 (m, 2H) 6.96 (dd, 1H)7.05-7.10 (m, 1H) 7.14 (d, 1H) 7.23 (d, 1H) 7.32-7.39 (m, 2H) 11.87 (s,1H); MS (ES−) m/z 396 [M−H]⁻

Example 251-[3-(oxetan-3-ylmethoxy)-4-phenoxyphenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.205 g, 0.0017 mol) was added to a solutionof 1-{3-[(3-Oxetanyl)methoxy]-4-phenoxyphenyl}-3-phenylurea(Intermediate 37, 0.580 g, 0.0014 mol) in toluene (5.8 mL) at 0° C. Thereaction mixture was stirred at 110° C. for 16 h. The solvent wasevaporated under reduced pressure to obtain the crude product. The crudeproduct was purified using preparative HPLC purification by using 0.1%formic acid as a modifier and water:acetonitrile (0-100% gradientsystem) as a mobile phase to yield 0.0049 g of the title compound. ¹HNMR (400 MHz, DMSO-d6) δ ppm 3.12-3.25 (m, 1H) 4.09-4.19 (m, 4H)4.41-4.55 (m, 2H) 6.86-6.92 (m, 2H) 6.99-7.10 (m, 2H) 7.20-7.17 (m, 1H)7.25-7.52 (m, 8H) 12.08 (s, 1H); MS (ES−) m/z 458 [M−H]⁻

Example 261-methyl-3-[4-phenoxy-3-(propan-2-yloxy)phenyl]-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.043 g, 0.37 mmol) was added to a solutionof 1-methyl-3-[4-phenoxy-3-(propan-2-yloxy)phenyl]urea (Intermediate 40,0.103 g, 0.34 mmol) in Toluene (1.3 mL) at 0° C. The reaction mixturewas heated at 110° C. for 16 h. The solvent was evaporated under reducedpressure to obtain the crude product. The crude product was purified byusing preparative HPLC purification with 0.1% ammonia as modifier andwater:acetonitrile (0-100% gradient system) as a mobile phase to yield0.035 g (27% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δppm 1.13 (d, 6H) 3.16 (s, 3H) 4.40-4.52 (m, 1H) 6.88-6.93 (m, 3H)7.04-7.11 (m, 2H) 7.16-7.21 (d, 1H) 7.32-7.38 (m, 2H) 11.75 (s, 1H); MS(ES−) m/z 368 [M−H]⁻

Example 271-[4-phenoxy-3-(propan-2-yloxy)phenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.115 g, 0.0010 mol) was added to thesolution of 1-[4-phenoxy-3-(propan-2-yloxy)phenyl]-3-phenylurea(Intermediate 41, 0.343 g, 0.0009 mol) in toluene (3.4 mL) at 0° C. Thereaction mixture was heated at 110° C. for 16 h. The solvent wasevaporated under reduced pressure. The crude product was purified usingpreparative HPLC purification with 0.1% ammonia as modifier andwater:acetonitrile (0-100% gradient system) as a mobile phase to yield0.009 g (2% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δppm 1.13 (d, 6H) 4.40-4.52 (m, 1H) 6.86-6.92 (m, 2H) 6.96 (dd, 1H)7.04-7.11 (m, 2H) 7.23 (d, 1H) 7.30-7.52 (m, 7H) 12.01 (s, 1H); MS (ES−)m/z 430 [M−H]⁻

Example 281-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-methyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.023 g, 0.199 mmol) was added to a solutionof 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-methylurea (Intermediate44, 0.062 g, 0.196 mmol) in Toluene (0.60 mL) at 0° C. The reactionmixture was heated at 110° C. for 16 h. The solvent was evaporated underreduce pressure and the crude product was purified on preparative HPLCusing 0.1% ammonium acetate as modifier and water:acetonitrile (0-100%gradient system) as a mobile phase in prep HPLC purification to yield0.027 g (36% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δppm 3.15 (s, 3H) 3.18 (s 3H) 3.52 (t, 2H) 4.03 (t, 2H) 6.90-6.96 (m, 3H)7.03-7.12 (m, 2H) 7.18-7.21 (m, 1H) 7.33-7.40 (m, 2H) 11.86 (s, 1H); MS(ES−) m/z 384 [M−H]⁻

Example 291-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.045 g, 0.0003 mol) was added to thesolution of 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-phenylurea(Intermediate 45, 0.135 g, 0.0003 mol) in toluene (1.30 mL) understirring at 0° C. The reaction mixture was heated at 110° C. for 16 h.The solvent was evaporated under reduced pressure to obtain the crudeproduct. The crude product was purified using preparative HPLC by using0.1% ammonium acetate as a modifier and water:acetonitrile (0-100%gradient system) as a mobile phase to yield 0.012 g (7% yield) of thetitle compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.18 (s, 3H) 3.53 (t,2H) 4.06 (t, 2H) 6.90-6.96 (m, 2H) 6.97-7.02 (m, 1H) 7.04-7.12 (m, 2H)7.25 (d, 1H) 7.32-7.53 (m, 7H) 12.05 (s, 1H); MS (ES−) m/z 446 [M−H]⁻

Example 301-[3-(benzyloxy)-4-phenoxyphenyl]-3-methyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.072 g, 0.63 mmol) was added to the solutionof 1-[3-(benzyloxy)-4-phenoxyphenyl]-3-methylurea (Intermediate 48,0.200 g, 0.574 mmol) in Toluene (2.0 mL) at 0° C. The reaction mixturewas heated at 110° C. for 16 h. The solvent was evaporated under reducedpressure. The crude was purified by preparative HPLC using 3 mM ammoniumacetate as modifier and water:acetonitrile (0-100% gradient system) as amobile phase to yield 0.030 g (12% yield) of the title compound. ¹H NMR(400 MHz, DMSO-d6) δ ppm 3.15 (s, 3H) 5.01 (s, 2H) 6.90-6.97 (m, 3H)7.06-7.20 (m, 4H) 7.25-7.32 (m, 4H) 7.33-7.40 (m, 2H) 11.87 (s, 1H); MS(ES−) m/z 416 [M−H]⁻

Example 311-methyl-3-(1-phenyl-1H-indazol-5-yl)-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.035 g, 0.304 mmol) was added to thesolution of (Intermediate 49, 0.075 g, 0.282 mmol) in Toluene (0.75 mL)at 0° C. The reaction mixture was heated at 110° C. for 16 h. Thesolvent was evaporated under reduce pressure. The crude product waspurified using preparative HPLC purification with 0.1% ammonia in waterand 100% Acetonitrile as a mobile phase to yield 0.055 g (58% yield) ofthe title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (s, 3H)7.40-7.48 (m, 2H) 7.58-7.66 (m, 2H) 7.78-7.84 (m, 2H) 7.86-7.93 (m, 2H)8.47 (d, 1H) 11.87 (s, 1H); MS (ES−) m/z 334 [M−H]−

Example 321-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-methyl-1,3,5-triazinane-2,4,6-trione

In a 10 ml seal tube flask previously equipped with a magnetic stirrerand nitrogen balloon, ethylcarbonyl isocyanate (0.033 g, 0.29 mmol) wasadded drop wise to a solution of1-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-methylurea (Intermediate 50,0.070 g, 0.24 mmol) in dry toluene (0.7 mL) at 25° C. The reactionmixture was heated at 110° C. for 16 h. The reaction mixture wasconcentrated under reduced pressure to obtain the crude product. Thecrude product was purified on preparative HPLC using 0.1% ammoniumacetate as a modifier and water:acetonitrile (0-100% as a gradientsystem) as mobile phase to yield 0.017 g (19% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 3H) 3.16 (s, 3H) 3.65(s, 3H) 6.73-6.79 (m, 2H) 6.87-6.91 (m, 1H) 6.98-7.07 (m, 2H) 7.28-7.35(m, 2H) 11.87 (s, 1H); MS (ES−) m/z 354 [M−H]⁻

Example 331-(2-methoxy-3-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethylcarbonyl isocyanate (0.138 g, 0.0011 mol) was added to a solutionof 1-(2-methoxy-3-methyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 53,0.380 g, 0.0010 mol) in toluene (3.80 mL) under stirring at 0° C. Thereaction mixture was heated at 110° C. for 16 h. The solvent wasevaporated under reduced pressure and the crude product was purified bypreparative HPLC using 0.1% ammonia as a modifier and water:acetonitrile(0-100% as a gradient system) as a mobile phase to yield 0.094 g (20%yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.17 (s,3H) 3.71 (s, 3H) 6.70 (d, 1H) 6.97-7.05 (m, 2H) 7.13-7.19 (m, 1H) 7.23(d, 1H) 7.37-7.53 (m, 7H) 12.11 (s, 1H); MS (ES−) m/z 416 [M−H]−

Example 341-[3-methyl-4-(phenylsulfanyl)phenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a 30 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.150 g, 0.0014 mol) was added to a solutionof 1-[3-methyl-4-(phenylsulfanyl)phenyl]-3-phenylurea (Intermediate 54,0.400 g, 0.0011 mol) in toluene (4.00 mL) stirred at 0° C. The reactionmixture was stirred at 110° C. for 16 h. The solvent was evaporatedunder reduced pressure to obtain the crude product. The crude productwas purified on combi flash chromatography by using 100% Ethyl acetateas a mobile phase and 60-120 silica as stationary phase. The obtainedproduct was further purified by preparative HPLC purification, using 5mM ammonium bicarbonate as a modifier and water:Acetonitrile (0-100%gradient system) as a mobile phase to yield 0.020 g (4% yield) of thetitle compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3H) 7.15-7.25(m, 2H) 7.30-7.53 (m, 11H) 12.01 (s, 1H); MS (ES−) m/z 402 [M−H]⁻

Example 351-(3-Methyl-1-phenyl-1H-indol-5-yl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

To a solution 1-(3-methyl-1-phenyl-1H-indol-5-yl)-3-phenylurea(Intermediate 57, 0.310 g, 0.00090 mol) in toluene (3.10 mL), was addedethoxycarbonyl isocyanate (0.209 g, 0.00180 mol) at 0° C. under nitrogenatmosphere. The resulting reaction mixture was heated at 110° C. for 16h under nitrogen atmosphere. The reaction mixture was concentrated underreduced pressure to obtain the crude product. The crude product waspurified on preparative chromatography using 0.1% ammonia as a modifierand water acetonitrile (0-100% gradient system) as mobile phases toobtain 0.015 g (4% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d6) δ ppm 2.33 (s, 3H) 7.16-7.22 (m, 1H) 7.36-7.52 (m, 6H)7.53-7.64 (m, 7H) 11.98 (s, 1H); MS (ES−) m/z 409 [M−H]⁻

Example 361-(1-Benzyl-3-methyl-1H-indol-5-yl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

To a solution of 1-(1-benzyl-3-methyl-1H-indol-5-yl)-3-phenylurea(Intermediate 60, 0.300 g, 0.0084 mol) in toluene (3.00 mL) was addedethoxycarbonyl isocyanate (0.194 g, 0.0016 mol) at 0° C. under nitrogenatmosphere. The resulting reaction mixture was heated at 110° C. for 16h under nitrogen atmosphere. The reaction mixture was concentrated underreduce pressure to obtained the crude product. The crude product waspurified on preparative chromatography using 5 mM ammoniumbicarbonate+0.05% ammonia as a modifier in water acetonitrile (0-100 asa gradient system) as mobile phases to obtain 0.016 g (4% yield) of thetitle compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H) 5.38 (s,2H) 7.04-7.09 (m, 1H) 7.21-7.27 (m, 3H) 7.28-7.36 (m, 3H) 7.37-7.52 (m,7H) 11.89 (s, 1H); MS (ES−) m/z 423 [M−H]⁻

Example 371-methyl-3-(3-methyl-1-phenyl-1H-indol-5-yl)-1,3,5-triazinane-2,4,6-trione

To a solution of 1-methyl-3-(3-methyl-1-phenyl-1H-indol-5-yl)urea(Intermediate 61, 0.070 g, 0.00025 mol) in toluene (0.70 mL) was addedethoxycarbonyl isocyanate (0.057 g, 0.00050 mol) at 0° C. under nitrogenatmosphere. The resulting reaction mixture was heated at 110° C. for 16h under nitrogen atmosphere. The reaction mixture was concentrated underreduced pressure to obtained the crude product. The crude product waspurified on preparative chromatography using (5 mM ammoniumbicarbonate+0.1% ammonia as a modifier) in water acetonitrile (0-100%gradient system) as mobile phases to obtained 0.030 g (34% yield) of thetitle compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 3.17 (s,3H) 7.08-7.13 (m, 1H) 7.35-7.44 (m, 1H) 7.52-7.64 (m, 7H) 11.75 (s, 1H);MS (ES+) m/z 349 [M+H]⁺

Example 381-(1-benzyl-3-methyl-1H-indol-5-yl)-3-methyl-1,3,5-triazinane-2,4,6-trione

In a 10 ml seal tube previously equipped with a magnetic stirrer,ethoxycarbonyl isocyanate (0.078 g, 0.00068 mol) was added to a solutionof 1-(1-benzyl-3-methyl-1H-indol-5-yl)-3-methylurea (Intermediate 62,0.100 g, 0.00034 mol) in toluene (1 mL) at 0° C. under N₂(g). Thereaction mixture was heated at 110° C. for 16 h under N₂(g). Thereaction mixture was concentrated under reduce pressure to obtainedcrude product. The crude product was purified by preparative HPLCpurification with 5 mM ammonium bicarbonate+0.1% ammonia as modifier andwater acetonitrile (0-100% gradient system) as a mobile phase to yield0.067 g (54% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δppm 2.25 (s, 3H) 3.15 (s, 3H) 5.38 (s, 2H) 6.95-7.02 (m, 1H) 7.21-7.28(m, 3H) 7.28-7.38 (m, 3H) 7.41-7.48 (m, 2H) 11.75 (s, 1H); MS (ES+) m/z363 [M+H]⁺

Example 391-(3-chloro-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

To a 10 ml microwave tube previously equipped with a magnetic stirrer,1-(3-chloro-4-phenoxyphenyl)-3-phenylurea (Intermediate 63, 0.150 g,0.0004 mol) and Bromobenzene (1.50 ml) was added and cooled to 0° C.Ethoxycarbonyl isocyanate (0.101 g, 0.0008 mol) was added and reactionmixture was allowed to reach to room temperature. The resulting reactionmixture was heated at 150° C. for 2 hours in a microwave oven. Thesolvent was evaporated under reduced pressure to obtain the crudeproduct. The crude product was purified by preparative HPLC using 0.1%formic acid as modifier in water:acetonitrile (0-100% gradient system)as a mobile phase to yield 0.010 g (5.5% yield) of the title compound.¹H NMR (400 MHz, DMSO-d6) δ ppm 6.99-7.05 (m, 2H) 7.06-7.13 (m, 1H)7.15-7.22 (m, 1H) 7.30-7.38 (m, 3H) 7.38-7.51 (m, 5H) 7.64-7.69 (m, 1H)12.10 (s, 1H); MS (ES−) m/z 406 [M−H]⁻

Example 401-(3-methyl-4-phenoxyphenyl)-3-(5-methylthiophen-2-yl)-1,3,5-triazinane-2,4,6-trione

In a microwave tube previously equipped with a magnetic stirrer1-(3-methyl-4-phenoxyphenyl)-3-(5-methylthiophen-2-yl)urea (Intermediate64, 0.200 g, 0.00059 mol) was dissolved in Chlorobenzene (2.0 ml) andcooled to 0° C. Ethyoxy carbonyl isocyanate (0.136 g, 0.00118 mol) wasadded to the mixture and the reaction mixture was allowed to reach roomtemperature and then heated at 130° C. for 4 hours in a microwave oven.The solvent was evaporated under reduced pressure to obtain the crudeproduct. The crude product was purified by preparative HPLC (55-100%Acetonitrile:Methanol (1:1) in water [0.1% Formic acid]) to yield 0.035g (14% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm2.19 (s, 3H), 3.95 (s, 3H), 6.66-6.70 (m, 1H), 6.77-6.81 (m, 1H)6.85-6.91 (m, 1H) 6.92-6.98 (m, 2H), 7.08-7.16 (m, 2H), 7.25 (s, 1H),7.34-7.41 (m, 2H), 11.96 (s, 1H); MS (ES−) m/z 406 [M−H]⁻

Example 411-(3-methyl-4-phenoxyphenyl)-3-(4-methylphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer1-(3-methyl-4-phenoxyphenyl)-3-(4-methylphenyl)urea (Intermediate 77,0.23 g, 0.0006 mol) and bromobenzene (2.3 ml) was added and cooled to 0°C. Ethoxy carbonyl isocyanate (0.15 g, 0.0013 mol) was added andresulting reaction mixture was allowed to reach RT and then heated at150° C. for 2 h in a microwave synthesizer. The solvent was evaporatedunder reduced pressure to obtain crude product that was purified bypreparative HPLC (40-100% Acetonitrile in water [0.1% Formic acid]) toyield 0.023 g (8% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d6) δ ppm 11.97 (s, 1H), 7.42-7.35 (m, 2H), 7.32-7.28 (m, 1H),7.27-7.22 (m, 3H), 7.22-7.08 (m, 3H), 6.98-6.93 (m, 2H), 6.93-6.85 (m,1H), 2.32 (s, 3H), 2.19 (s, 3H); MS (ES−) m/z 400 [M−H]⁻

Example 421-(4-benzyl-3-methylphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

1-(4-benzyl-3-methylphenyl)-3-phenylurea (Intermediate 74, 0.50 g,0.0015 mol) and bromobenzene (5 ml) was added to a microwave vial with amagnetic stirrer and cooled to 0° C. Ethoxy carbonyl isocyanate (0.36 g,0.0031 mol) was added and reaction mixture was allowed to reach RT. Theresulting reaction mixture was heated at 150° C. for 2 hours in amicrowave oven. The solvent was evaporated under reduced pressure andthe crude product was purified by using preparative HPLC (15-100%acetonitrile in water [0.1% Formic acid]) to yield 40 mg (6% yield) ofthe title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (s, 1H),7.53-7.29 (m, 7H), 7.26-7.11 (m, 6H), 4.00 (s, 2H), 2.25 (s, 3H); MS(ES−) m/z 384 [M−H]⁻

Example 431-(3-chlorophenyl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer,1-(3-chlorophenyl)-3-(3-methyl-4-phenoxyphenyl)urea (Intermediate 75,0.30 g, 0.0008 mol) was added to bromobenzene (3.0 ml) and the mixturewas cooled to 0° C. Ethoxy carbonyl isocyanate (0.19 g, 0.0017 mol) wasadded and resulting reaction mixture was allowed to reach RT and thenheated at 150° C. for 2 h in microwave oven. The solvent was evaporatedunder reduce pressure to obtain crude product which was purified bypreparative HPLC (20-100% Acetonitrile in water [0.1% Formic acid]) toyield 0.019 g (5% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d6) δ ppm 12.12 (s, 1H), 7.57-7.51 (m, 3H), 7.46-7.37 (m, 3H), 7.32(d, J=2.5 Hz, 1H), 7.24-7.11 (m, 2H), 7.02-6.91 (m, 3H), 2.24 (s, 3H);MS (ES−) m/z 420 [M−H]⁻

Example 441-(3-methyl-4-phenoxyphenyl)-3-[3-(trifluoromethoxy)phenyl]-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer1-(3-methyl-4-phenoxyphenyl)-3-[3-(trifluoromethoxy)phenyl]urea(Intermediate 76, 0.40 g, 0.0009 mol) was added to bromobenzene (4.0 ml)the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (0.22 g,0.0019 mol) was added and reaction mixture was allowed to reach RT andthen heated at 150° C. for 2 h in a microwave synthesizer. The solventwas evaporated under reduced pressure to obtain crude product which waspurified by preparative HPLC (25-100% Acetonitrile in water [5 mMAmmonium bicarbonate+0.1% NH3]) to yield 0.039 g (8% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.13 (s, 1H), 7.69-7.60 (m,1H), 7.52-7.37 (m, 5H), 7.32 (d, J=2.5 Hz, 1H), 7.24-7.11 (m, 2H),7.02-6.91 (m, 3H), 2.24 (s, 3H); MS (ES−) m/z 470 [M−H]⁻

Example 451-(4-fluorophenyl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave tube previously equipped with a magnetic stirrer1-(4-fluorophenyl)-3-(3-methyl-4-phenoxyphenyl)urea (Intermediate 65,0.100 g, 0.0002 mol) in bromobenzene (1.00 ml) was cooled to 0° C.Ethoxy carbonyl isocyanate was added and reaction mixture was allowed toreach RT and then heated at 150° C. for 2 h in microwave oven. Thesolvent was evaporated under reduced pressure and the crude product waspurified by preparative HPLC (20-100% Acetonitrile in water [0.1% formicacid] to yield 0.011 g (9% yield) of the title compound. ¹H NMR (400MHz, DMSO-d6) δ 2.23 (s, 3H), 6.90-7.01 (m, 3H), 7.11-7.24 (m, 2H),7.28-7.38 (m, 3H), 7.38-7.48 (m, 4H), 12.07 (s, 1H); MS (ES−) m/z 404[M−H]⁻

Example 461-(1-benzofuran-5-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

Sodium hydride (60% in mineral oil, 7.25 mg, 0.18 mmol).) was added to amicrowave vial containing a magnetic stirring bar. The vial was sealedand put under an inert atmosphere and the sodium hydride was washed withpentane. The pentane was thereafter removed, DMF (1 ml) was added andthe dispersion was cooled to 0° C.1-(benzofuran-5-yl)-3-(3-methyl-4-phenoxy-phenyl)urea (Intermediate 66,26 mg, 0.07 mmol) was dissolved in DMF (1.5 ml) and added dropwise tothe reaction vessel. The ice bath was removed and the reaction mixturewas stirred for another 10 min. The solution was again cooled to 0° C.and ethoxycarbonyl isocyanate (11 μl, 0.11 mmol) was thereafter added,the ice bath was removed and the reaction mixture was stirred for 5additional minutes before addition of water and EtOAc. The solvents wereremoved under reduced pressure. The crude from the water phase waspurified by preparative RP-HPLC (30-90% acetonitrile in water [0.05%HCOOH]) to yield 8.8 mg (28% yield) of the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.01 (br. s, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.71-7.64(m, 2H), 7.43-7.36 (m, 2H), 7.35-7.28 (m, 2H), 7.21 (dd, J=8.5, 2.5 Hz,1H), 7.17-7.10 (m, 1H), 7.05-7.02 (m, 1H), 7.00-6.93 (m, 2H), 6.91 (d,J=8.6 Hz, 1H), 2.22 (s, 3H); ESI+m/z 428 (M+H)+

Example 471-(1H-indol-5-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

1-(1H-indol-5-yl)-3-(3-methyl-4-phenoxy-phenyl)urea (Intermediate 67, 21mg, 0.06 mmol) was dispersed in toluene (0.5 ml) in a microwave vial(0.5-2 ml), ethoxycarbonyl isocyanate (6 μl, 0.06 mmol) was added andthe mixture was heated at 110° C. in an oil bath for 5 h and wasthereafter left at room temperature overnight. The crude wasconcentrated at reduced pressure and the product was purified bypreparative RP-HPLC (20-80% acetonitrile in water [0.05% HCOOH]) toyield 2 mg (6% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δppm 11.91 (br. s, 1H), 11.25 (s, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.45-7.36(m, 4H), 7.36-7.32 (m, 1H), 7.22 (dd, J=8.6, 2.4 Hz, 1H), 7.13 (t, J=7.4Hz, 1H), 7.04 (dd, J=8.6, 1.8 Hz, 1H), 6.99-6.94 (m, 2H), 6.91 (d, J=8.6Hz, 1H), 6.50-6.45 (m, 1H), 2.21 (s, 3H); MS(ESI+) m/z 427 (M+H)+

Example 481-(2H-1,3-benzodioxol-5-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

Sodium hydride (60% in mineral oil, 33 mg, 0.82 mmol) was added to amicrowave vial containing a magnetic stirring bar. The vial was sealedand put under an inert atmosphere and the sodium hydride was washed withpentane. The pentane was thereafter removed, DMF (1 ml) was added andthe dispersion was cooled to 0° C.1-(1,3-benzodioxol-5-yl)-3-(3-methyl-4-phenoxy-phenyl)urea (Intermediate68, 119 mg, 0.33 mmol) was dissolved in DMF (2 ml) and added dropwise tothe reaction vessel. The ice bath was removed and the reaction mixturewas stirred for another 10 min. The solution was again cooled to 0° C.and ethoxycarbonyl isocyanate (51 μl, 0.49 mmol) was thereafter added,the ice bath was removed and the reaction mixture was stirred for 5additional minutes before addition of water and EtOAc. The phases wereseparated and concentrated under reduced pressure. The crude productoriginating from the water phase was purified by preparative RP-HPLC(20-80% acetonitrile in water [0.05% HCOOH]) to yield 10 mg (7% yield)of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (s, 1H),7.44-7.36 (m, 2H), 7.30 (d, J=1.9 Hz, 1H), 7.18 (dd, J=8.8, 2.3 Hz, 1H),7.14 (t, J=7.4 Hz, 1H), 7.01-6.94 (m, 4H), 6.91 (d, J=8.6 Hz, 1H), 6.85(dd, J=8.2, 2.0 Hz, 1H), 6.09 (s, 2H), 2.22 (s, 3H). MS(ESI+) m/z 432(M+H)+

Example 491-(1H-indol-4-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

1-(1H-indol-4-yl)-3-(3-methyl-4-phenoxy-phenyl)urea (Intermediate 69,118 mg, 0.33 mmol) was dispersed in toluene (2.5 ml) in a microwavevial, ethoxycarbonyl isocyanate (34 μl, 0.33 mmol) was added and themixture was heated at 110° C. for 5 h and was thereafter left at roomtemperature overnight. The crude was concentrated at reduced pressureand the product was purified by preparative RP-HPLC (40-80% acetonitrilein water [0.05% HCOOH]) to yield 5 mg (3.5% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (s, 1H), 11.26 (s, 1H),7.45 (d, J=8.1 Hz, 1H), 7.42-7.35 (m, 4H), 7.26 (dd, J=8.6, 2.4 Hz, 1H),7.17-7.10 (m, 2H), 7.01 (d, J=7.5 Hz, 1H), 6.98-6.93 (m, 2H), 6.91 (d,J=8.6 Hz, 1H), 6.59-6.54 (m, 1H), 2.21 (s, 3H); MS(ESI+) m/z 427 (M+H)+

Example 501-(3-methoxyphenyl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

Sodium hydride (60% in mineral oil, 33 mg, 0.83 mmol) was weighed up ina microwave vial and a stirring bar was added. was added to a microwavevial containing a magnetic stirring bar. The vial was sealed and putunder an inert atmosphere and the sodium hydride was washed withpentane. The pentane was thereafter removed, DMF (2 ml) was added andthe dispersion was cooled to 0° C.1-(3-methoxyphenyl)-3-(3-methyl-4-phenoxy-phenyl)urea (Intermediate70,115 mg, 0.33 mmol) was dissolved in DMF (2 ml) and added dropwise tothe reaction vessel. The ice bath was removed and the reaction mixturewas stirred for another 10 min. The solution was again cooled to 0° C.and ethoxycarbonyl isocyanate (51 μl, 0.50 mmol) was added, the ice bathwas removed and the reaction mixture was stirred for 5 additionalminutes before addition of water and EtOAc. The phases were separatedand concentrated under reduced pressure. The product in the concentratedwater phase was purified by preparative RP-HPLC (40-80% acetonitrile inwater [0.05% HCOOH]) to yield 40 mg (29% yield) of the title compound.¹H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (s, 1H), 7.44-7.34 (m, 3H), 7.32(d, J=2.2 Hz, 1H), 7.22-7.17 (m, 1H), 7.17-7.10 (m, 1H), 7.03-6.94 (m,5H), 6.92 (d, J=8.6 Hz, 1H), 3.77 (s, 3H), 2.22 (s, 3H); MS(ESI+) m/z418 (M+H)+

Example 511-(2-methoxyphenyl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

Sodium hydride (60% in mineral oil, 34 mg, 0.85 mmol) was added to amicrowave vial containing a magnetic stirring bar. The vial was sealedand put under an inert atmosphere and the sodium hydride was washed withpentane. The pentane was thereafter removed, DMF (2 ml) was added andthe dispersion was cooled to 0° C.1-(2-methoxyphenyl)-3-(3-methyl-4-phenoxy-phenyl)urea (Intermediate 71,119 mg, 0.34 mmol) was dissolved in DMF solution (2 ml) and was addeddropwise to the reaction vessel. The ice bath was removed and thereaction mixture was stirred for another 10 min. The solution was againcooled to 0° C. and ethoxycarbonyl isocyanate (53 μl, 0.51 mmol) wasadded, the ice bath was removed and the reaction mixture was stirred for5 additional minutes before addition of water and EtOAc. The phases wereseparated and concentrated by reduced pressure. The crude productoriginating from the water phase was purified by preparative RP-HPLC(40-80% acetonitrile in water [0.05% HCOOH]) to yield 54 mg (37% yield)of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (br. s,1H), 7.46-7.30 (m, 5H), 7.20 (dd, J=8.6, 2.5 Hz, 1H), 7.18-7.10 (m, 2H),7.03 (td, J=7.6, 1.2 Hz, 1H), 6.99-6.93 (m, 2H), 6.91 (d, J=8.6 Hz, 1H),3.79 (s, 3H), 2.22 (s, 3H); MS(ESI+) m/z 418 (M+H)+

Example 521-(3-methoxy-4-phenoxyphenyl)-3-(3-methoxyphenyl)-1,3,5-triazinane-2,4,6-trione

Sodium hydride (60% in mineral oil, 62 mg, 1.5 mmol) was added to amicrowave vial containing a magnetic stirring bar. The vial was sealedand put under an inert atmosphere and the sodium hydride was washed withpentane. The pentane was thereafter removed, and the vessel was cooledto 0° C. 1-(3-methoxy-4-phenoxy-phenyl)-3-(3-methoxyphenyl)urea(Intermediate 72, 225 mg, 0.617 mmol) was dissolved in DMF (2 ml) andadded dropwise to the reaction vessel containing the sodium hydride. Theice bath was removed and the reaction mixture was stirred for another 10min. The solution was again cooled to 0° C. and ethoxycarbonylisocyanate (96 μl, 0.93 mmol) was added, the ice bath was removed andthe reaction mixture was stirred for 5 additional minutes beforeaddition of water and EtOAc. The phases were separated and concentratedunder reduced pressure. The crude product from the water phase waspurified by preparative RP-HPLC (30-80% acetonitrile in water [0.05%HCOOH]) to yield 77 mg (28%) of the title compound. ¹H NMR (400 MHz,DMSO-d6) δ ppm 12.02 (br. s, 1H), 7.42-7.31 (m, 3H), 7.23 (d, J=2.3 Hz,1H), 7.10-6.93 (m, 6H), 6.92-6.86 (m, 2H), 3.77 (s, 3H), 3.73 (s, 3H)MS(ESI+) m/z 434 (M+H)+

Example 531-(3-methoxy-4-phenoxyphenyl)-3-(4-methoxyphenyl)-1,3,5-triazinane-2,4,6-trione

Sodium hydride (60% in mineral oil, 36 mg, 0.90 mmol) was added to amicrowave vial containing a magnetic stirring bar. The vial was sealedand put under an inert atmosphere and the sodium hydride was washed withpentane. The pentane was removed and the vial cooled to 0° C.1-(3-methoxy-4-phenoxy-phenyl)-3-(4-methoxyphenyl)urea (Intermediate 73,131 mg, 0.359 mmol) was dissolved in DMF solution (2 ml) and was addeddropwise to the reaction vessel containing the sodium hydride. The icebath was removed and the reaction mixture was stirred for another 10min. The solution was again cooled to 0° C. and ethoxycarbonylisocyanate (56 μl, 0.54 mmol) was added, the ice bath was removed andthe reaction mixture was stirred for 5 additional minutes beforeaddition of water and EtOAc. The phases were separated and concentratedunder reduced pressure. The crude product from the water phase waspurified by preparative RP-HPLC (30-80% acetonitrile in water [0.05%HCOOH]) to yield 11 mg (7% yield) of the title compound. ¹H NMR (400MHz, DMSO-d6) δ ppm 11.98 (br. s, 1H), 7.38-7.32 (m, 2H), 7.31-7.25 (m,2H), 7.24 (d, J=2.3 Hz, 1H), 7.10-7.04 (m, 2H), 7.04-6.99 (m, 2H),6.99-6.96 (m, 1H), 6.92-6.86 (m, 2H), 3.79 (s, 3H), 3.73 (s, 3H);MS(ESI+) m/z 434 (M+H)+

Example 541-(2,5-dimethyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer1-(2,5-dimethyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 79, 0.20 g,0.0006 mol) and chlorobenzene (2.0 ml) was added. The solution wascooled to 0° C. and Ethoxy carbonyl isocyanate (0.20 g, 0.0018 mol) wasadded and reaction mixture was allowed to reach RT and then heated at130° C. for 2 hours in a microwave synthesizer. The solvent wasevaporated under reduced pressure and the crude product was purified bypreparative HPLC (45-100% Acetonitrile in water [0.1% Formic acid]) toyield 0.093 g (38%) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δppm 12.07 (s, 1H), 7.54-7.45 (m, 3H), 7.45-7.37 (m, 4H), 7.30 (s, 1H),7.18-7.10 (m, 1H), 6.99-6.92 (m, 2H), 6.82 (s, 1H), 2.17 (s, 3H), 2.10(s, 3H); MS(ESI−) m/z 400 (M−H)−

Example 551-methyl-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer1-methyl-3-(3-methyl-4-phenoxyphenyl)urea (Intermediate 78, 0.35 g,0.0013 mol) and bromobenzene (3.5 ml) was added and the solution cooledto 0° C. Ethoxy carbonyl isocyanate (0.31 g, 0.0027 mol) was added andreaction mixture was allowed to reach RT and then heated at 150° C. for2 h in a microwave synthesizer. The solvent was evaporated under reducedpressure and the crude product was purified by preparative HPLC (30-100%Acetonitrile in water [0.1% Formic acid]) to yield 0.070 g (15% yield)of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (s, 1H),7.47-7.37 (m, 2H), 7.30-7.27 (m, 1H), 7.21-7.11 (m, 2H), 7.04-6.96 (m,2H), 6.95-6.88 (m, 1H), 3.16 (s, 3H), 2.22 (s, 3H); MS(ESI−) m/z 324(M−H)−

Example 561-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methylphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methylphenyl)urea(Intermediate 80, 0.20 g, 0.0005 mol) and bromobenzene (2.0 ml) wasadded and the solution cooled to 0° C., Ethoxy carbonyl isocyanate (0.17g, 0.0015 mol) was added and reaction mixture was heated at 150° C. for3 h in a microwave synthesizer. The solvent was evaporated under reducedpressure and the crude product was purified by preparative HPLC (40-100%Acetonitrile in water [0.1% Formic acid]) to yield 0.032 g (13% yield)of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (s, 1H), δ7.42-7.33 (m, 2H), 7.33-7.19 (m, 5H), 7.13-7.03 (m, 2H), 7.02-6.90 (m,3H), 4.06 (t, J=4.6 Hz, 2H), 3.53 (t, J=4.5 Hz, 2H), 3.19 (s, 3H), 2.36(s, 3H); MS(ESI−) m/z 460 (M−H)−

Example 571-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methylphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methylphenyl)urea(Intermediate 81, 0.29 g, 0.0007 mol) and bromobenzene (2.90 ml) wasadded and cooled to 0° C. Ethoxy carbonyl isocyanate (0.25 g, 0.0022mol) was added and the reaction mixture was heated at 150° C. for 2 h.The solvent was evaporated under reduced and the crude product waspurified by preparative HPLC (30-100% Acetonitrile in water [0.1% Formicacid]) to yield 0.030 g (8% yield) of the title compound. ¹H NMR (400MHz, DMSO-d6) δ ppm 12.04 (s, 1H), 7.42-7.33 (m, 3H), 7.30-7.22 (m, 2H),7.21-7.15 (m, 2H), 7.14-7.06 (m, 2H), 7.04-6.97 (m, 1H), 6.97-6.91 (m,2H), 4.06 (t, J=4.5 Hz, 2H), 3.54 (t, J=4.4 Hz, 2H), 3.19 (s, 3H), 2.36(s, 3H); MS(ESI−) m/z 460 (M−H)−

Example 581-(3-chlorophenyl)-3-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-chlorophenyl)urea(Intermediate 82, 0.12 g, 0.0002 mol) and bromobenzene (1.2 ml) wasadded and cooled to 0° C., Ethoxy carbonyl isocyanate (0.060 g, 0.0005mol) was added and the reaction mixture was heated to 150° C. for 2 h.The solvent was evaporated under reduced pressure and the crude productwas purified by preparative HPLC (15-100% Acetonitrile in water [5 mMAmmonium bicarbonate+0.1% NH3]) to yield 8.5 mg (6% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.14 (s, 1H), 7.60-7.50 (m,3H), 7.42-7.32 (m, 3H), 7.20 (d, J=2.3 Hz, 1H), 7.12-7.05 (m, 2H),7.00-6.90 (m, 3H), 4.06 (t, J=4.6 Hz, 2H), 3.53 (t, J=4.5 Hz, 2H), 3.18(s, 3H); MS(ESI−) m/z 480 (M−H)−

Example 591-(4-chlorophenyl)-3-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer,1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-chlorophenyl)urea(Intermediate 83, 0.22 g, 0.0005 mol) and bromobenzene (2.20 ml) wasadded and the solution was cooled to 0° C. Ethoxy carbonyl isocyanate(0.18 g, 0.00159 mol) was added and the reaction mixture was heated at150° C. in a microwave synthesizer for 3 h. The solvent was evaporatedunder reduced pressure to obtain crude product that was purified bypreparative HPLC (40-100% Acetonitrile:Methanol (1:1) in water [0.1%Formic acid]) to yield 10 mg (3.8% yield) of the title compound. ¹H NMR(400 MHz, DMSO-d6) δ ppm 12.14 (s, 1H), 7.60-7.54 (m, 2H), 7.46-7.33 (m,4H), 7.22 (d, J=2.3 Hz, 1H), 7.13-7.05 (m, 2H), 7.00-6.91 (m, 3H), 4.06(t, J=4.6 Hz, 2H), 3.54 (t, J=4.5 Hz, 2H), 3.19 (s, 3H); MS(ESI−) m/z480 (M−H)−

Example 601-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methoxyphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methoxyphenyl)urea(Intermediate 84, 0.24 g, 0.0005 mol) and bromobenzene (2.4 ml) wasadded and the solution was cooled to 0° C. Ethoxy carbonyl isocyanate(0.27 g, 0.0023 mol) was added to the reaction mixture and it was heatedat 150° C. in a microwave synthesizer for 3 h. The solvent wasevaporated under reduced pressure to obtain crude product that waspurified by preparative HPLC (30-100% Acetonitrile in water [0.1% Formicacid]) to yield 16 mg (5% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d6) δ ppm 12.01 (s, 1H), 7.42-7.32 (m, 2H), 7.32-7.22 (m, 3H),7.15-6.91 (m, 7H), 4.07 (t, J=4.5 Hz, 2H), 3.81 (s, 3H), 3.54 (t, J=4.6Hz, 2H), 3.19 (s, 3H); MS(ESI−) m/z 476 (M−H)−

Example 611-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methoxyphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial, previously equipped with a magnetic stirrer,1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methoxyphenyl)urea(Intermediate 85, 0.25 g, 0.0006 mol) and bromobenzene (2.5 ml) wasadded and the solution was cooled to 0° C. Ethoxy carbonyl isocyanate(0.28 g, 0.0024 mol) was slowly added and reaction mixture was heated at150° C. for 3 h. The solvent was evaporated under reduced pressure andthe crude product was purified by preparative HPLC (45-100% Acetonitrilein water [0.1% Formic acid]) to yield 0.025 g (8% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.04 (s, 1H), 7.45-7.33 (m,3H), 7.25 (d, J=2.3 Hz, 1H), 7.15-7.01 (m, 2H), 7.05-6.91 (m, 6H), 4.07(t, J=4.6 Hz, 2H), 3.79 (s, 3H), 3.54 (t, J=4.6 Hz, 2H), 3.19 (s, 3H);MS(ESI−) m/z 476 (M−H)−

Example 621-[3-methyl-4-(2-methylphenoxy)phenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

n a microwave vial previously equipped with a magnetic stirrer,1-[3-methyl-4-(2-methylphenoxy)phenyl]-3-phenylurea (Intermediate 86,0.23 g, 0.0006 mol) in chlorobenzene (2.30 ml) was added and cooled to0° C. Ethoxy carbonyl isocyanate (0.23 g, 0.0020 mol) was added andreaction mixture was heated at 130° C. for 2 h. The solvent wasevaporated under reduced pressure and the crude product was purified bythe preparative HPLC (55-100% Acetonitrile:Methanol (1:1) in water [0.1%Formic acid]) to yield 9 mg (3% yield) of the title compound. ¹H NMR(400 MHz, DMSO-d6) δ ppm 11.93 (s, 1H), 7.52-7.40 (m, 3H), 7.40-7.32 (m,3H), 7.31-7.27 (m, 1H), 7.25-7.18 (m, 1H), 7.17-7.06 (m, 2H), 6.82 (d,J=7.9 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 2.27 (s, 3H), 2.21 (s, 3H);MS(ESI−) m/z 400 (M−H)−

Example 631-(3-methyl-4-phenoxyphenyl)-3-(1,3-thiazol-4-yl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer,1-(3-methyl-4-phenoxyphenyl)-3-(1,3-thiazol-4-yl)urea (Intermediate 87,0.30 g, 0.0009 mol) in bromobenzene (3.0 ml) was added and cooled to 0°C. Ethoxy carbonyl isocyanate (0.42 g, 0.0036 mol) was added at 0° C.and the reaction mixture was allowed to reach RT and then heated at 150°C. for 3 h in a microwave synthesizer. The solvent was evaporated underreduced pressure and the crude product was purified by Combi-flashchromatography using 45% ethyl acetate in hexanes as an eluent to yield16 mg (4% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm12.13 (s, 1H), 9.14 (d, J=2.2 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.45-7.32(m, 3H), 7.23 (dd, J=8.5, 2.6 Hz, 1H), 7.14 (t, J=7.4 Hz, 1H), 7.01-6.95(m, 2H), 6.93-6.88 (m, 1H), 2.22 (s, 3H); MS(ESI−) m/z 393 (M−H)−

Example 641-[4-(4-chlorophenoxy)phenyl]-3-methyl-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer, Ethoxycarbonyl isocyanate (0.074 g, 0.00065 mol) was added to a solution of1-[4-(4-chlorophenoxy)phenyl]-3-methylurea (Intermediate 88, 0.120 g,0.00043 mol) in Toluene (1.20 ml) at 0° C. The reaction mixture washeated at 110° C. for 16 h and quenched with ice-water (50 ml) andextracted with ethyl acetate (3×40 ml). The combined organic layer waswashed with brine (30 ml), dried over sodium sulfate and the solventremoved under reduced pressure to obtain 0.140 g (93% yield) of thetitle compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.15 (s, 3H) 7.06-7.15(m, 4H) 7.31-7.37 (m, 2H) 7.46-7.52 (m, 2H) 11.82 (s, 1H); MS (ES−) m/z344 [M−H]−

Example 651(3-chloro-4-phenoxyl)enyl)-3-methyl-1,3,5-triazinane-2,4,6-trione

1-(3-Chloro-4-phenoxyphenyl)-3-methylurea (Intermediate 89, 0.145 g,0.00052 mol) in bromobenzene (1.45 ml) was added to a microwave tubepreviously equipped with a magnetic stirrer and cooled to 0° C. Ethoxycarbonyl isocyanate (0.120 g, 0.00104 mol) was added and reactionmixture was heated at 150° C. for 2 h. The solvent was removed underreduced pressure and the crude product was purified by preparative HPLC(30-100% Acetonitrile in water [5 mM ammonium bicarbonate and 0.1%ammonia]) to yield 0.020 g (11% yield) of the title compound. ¹H NMR(400 MHz, DMSO-d6): δ11.86 (s, 1H), δ 7.64 (d, J=2.4 Hz, 1H), 7.45 (t,J=7.9 Hz, 2H), 7.32 (dd, J=8.7, 2.5 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H),7.11 (d, J=8.7 Hz, 1H), 7.05 (d, J=8.1 Hz, 2H), 3.15 (s, 3H). MS(ESI−)m/z 344.49 (M−H)−

Example 661-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(5-methylthiophen-2-yl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer wastaken1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(5-methylthiophen-2-yl)urea(Intermediate 90, 0.32 g, 0.0008 mol) and chlorobenzene (6.4 ml). Thesolution was cooled to 0° C. and Ethoxy carbonyl isocyanate (0.37 g,0.0032 mol) was added. The reaction mixture was allowed to reach roomtemperature and then heated at 130° C. for 3 h in an Anton paarmicrowave synthesizer-300. The solvent was evaporated under reducedpressure and the crude product was purified by preparative RP-HPLC(15-100% acetonitrile in water [10 mM Ammonium acetate]) to yield 5 mg(1.3% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm12.10 (s, 1H), 7.42-7.33 (m, 2H), 7.24 (d, J=2.0 Hz, 1H), 7.12-7.06 (m,2H), 6.99-6.93 (m, 3H), 6.87 (d, J=3.6 Hz, 1H), 6.74 (m, 1H), 4.06 (t,J=4.0 Hz, 2H), 3.53 (t, J=4.4 Hz, 2H), 3.19 (s, 3H), 2.46 (s, 3H). MS(ES−) m/z 466 [M−H]−

Example 671,3-bis(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer,1,3-bis(3-methyl-4-phenoxyphenyl)urea (Intermediate 91, 0.30 g, 0.0007mol) in Bromobenzene (3 ml) was added and the mixture was cooled to 0°C. Ethoxy carbonyl isocyanate (0.32 g, 0.0028 mol) was added and theresulting reaction mixture was allowed to reach room temperature andthen heated at 150° C. for 3 h in an Anton paar microwavesynthesizer-300. The solvent was evaporated under reduce pressure toobtain crude product. The crude product was purified by preparativeRP-HPLC (40-100% acetonitrile in water [0.1% formic acid]) to yield 52mg (14% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm12.05 (s, 1H), 7.46-7.37 (m, 4H), 7.33 (d, J=2.5 Hz, 2H), 7.21 (dd,J=8.8, 2.4 Hz, 2H), 7.15 (t, J=7.6 Hz, 2H), 7.02-6.90 (m, 6H), 2.11 (s,6H). MS(ESI−) m/z 492 [M−H]−

Example 681-(3-methyl-4-phenoxyphenyl)-3-(1-phenyl-1H-pyrazol-4-yl)-1,3,5-triazinane-2,4,6-trione

In a microwave tube previously equipped with a magnetic stirrer1-(3-methyl-4-phenoxyphenyl)-3-(1-phenyl-1H-pyrazol-4-yl)urea(Intermediate 93, 0.23 g, 0.0008 mol) in Bromobenzene (3.0 ml) was addedand the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (0.19 g,0.0017 mol) was added and the reaction mixture was allowed to reach roomtemperature and heated at 150° C. for 2 h in an Anton paar microwavesynthesizer-300. The solvent was evaporated under reduce pressure andthe crude product was purified by preparative RP-HPLC (25-100%acetonitrile in water [5 mM ammonium bicarbonate+0.1% NH₃]) to yield 52mg (19% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm12.15 (s, 1H), 8.67 (s, 1H), 7.88-7.83 (m, 3H), 7.62-7.50 (m, 2H),7.45-7.33 (m, 4H), 7.23 (d, J=8.4, 1H), 7.15 (t, J=7.2 Hz, 1H),7.03-6.91 (m, 3H), 2.24 (s, 3H). MS (ES−) m/z 452 [M−H]−

Example 691-(3-bromo-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer1-(3-bromo-4-phenoxyphenyl)-3-phenylurea (Intermediate 94, 0.50 g,0.0013 mol) in bromobenzene (5.0 ml) was added and the mixture wascooled to 0° C. Ethoxy carbonyl Isocyanate (0.60 g, 0.0052 mol) wasadded at 0° C. and the resulting reaction mixture was allowed to reachroom temperature and heated at 150° C. for 3 h in an Anton paarmicrowave synthesizer-300. The solvent was evaporated under reducedpressure and the crude product was purified by using preparative RP-HPLC(50-100% acetonitrile in water [0.1% formic acid]) to yield 5 mg (0.85%yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.11 (s,1H), 7.84 (d, J=2.4 Hz, 1H), 7.52-7.36 (m, 8H), 7.22 (app t, J=7.2 Hz,1H), 7.13-7.02 (m, 3H). MS (ES−) m/z 452 [M−H]−

Example 701-(2-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer1-(2-methyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 95, 0.20 g,0.0006 mol) in bromobenzene (2.0 ml) was added and the mixture wascooled to 0° C. Ethoxy carbonyl isocyanate (0.28 g, 0.0025 mol) wasadded and the reaction mixture was allowed to reach room temperature andheated at 150° C. for 3 h in an Anton paar microwave synthesizer-300.The solvent was evaporated under reduced pressure and the crude productwas purified by preparative RP-HPLC (40-100% acetonitrile in water [0.1%formic acid]) to yield 30 mg (yield 12%) of the title compound. ¹H NMR(400 MHz, DMSO-d6) δ ppm 12.06 (s, 1H), 7.53-7.31 (m, 8H), 7.19 (t,J=7.2 Hz, 1H), 7.12-7.05 (m, 2H), 6.98-6.83 (m, 2H), 2.15 (s, 3H). MS(ES−) m/z 386 [M−H]−

Example 711-(2-methyl-4-phenoxyphenyl)-3-(4-methylphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer1-(2-methyl-4-phenoxyphenyl)-3-(4-methylphenyl)urea (Intermediate 97,0.40 g, 0.0012 mol) in bromobenzene (4.0 ml) was added and the mixturewas cooled to 0° C. Ethoxy carbonyl isocyanate (0.55 g, 0.0048 mol) wasadded and reaction mixture was allowed to reach room temperature andheated at 150° C. for 3 h in an Anton paar microwave synthesizer-300.The solvent was removed under reduced pressure to obtain crude productthat was purified by preparative RP-HPLC (30-100% acetonitrile in water[0.1% formic acid]) to yield 12 mg (2% yield) of the title compound. ¹HNMR (400 MHz, DMSO-d6) δ ppm 12.03 (s, 1H), 7.48-7.40 (m, 2H), 7.34 (d,J=8.8 Hz, 1H), 7.27 (app s, 4H), 7.20 (t, J=7.2 Hz, 1H), 7.10-7.05 (m,2H), 6.95 (d, J=2.4 Hz, 1H), 6.88 (dd, J=8.4, 2.8 Hz, 1H), 2.35 (s, 3H),2.14 (s, 3H). MS (ES−) m/z 400 [M−H]−

Example 721-(1-benzofuran-4-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave tube previously equipped with a magnetic stirrer1-(1-benzofuran-4-yl)-3-(3-methyl-4-phenoxyphenyl)urea (Intermediate 98,0.25 g, 0.0006 mol) in bromobenzene (2.5 ml) was added and the mixturewas cooled to 0° C. Ethoxy carbonyl isocyanate (0.32 g, 0.0027 mol) wasadded at 0° C. and the reaction mixture was allowed to reach roomtemperature and heated at 150° C. for 3 h in an Anton paar microwavesynthesizer-300. The solvent was removed under reduced pressure toobtain the crude product that was purified by preparative RP-HPLC(20-100% acetonitrile in water [0.1% formic acid]) to yield 16 mg (5%yield) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.10 (s,1H), 8.03 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.42-7.38 (m, 4H),7.31-7.25 (m, 2H), 7.21-7.10 (m, 2H), 7.00-6.90 (m, 3H), 2.23 (s, 3H).MS (ES−) m/z 426 [M−H]−

Example 731-(1-benzofuran-7-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

In a microwave vial previously equipped with a magnetic stirrer,1-(1-benzofuran-7-yl)-3-(3-methyl-4-phenoxyphenyl)urea (Intermediate 99,0.50 g, 0.00139 mol) in bromobenzene (5.0 ml) was added and the mixturewas cooled to 0° C. Ethoxy carbonyl Isocyanate (0.64 g, 0.00558 mol) wasadded at 0° C. and reaction mixture was allowed to reach roomtemperature and heated at 150° C. for 3 h in an Anton paar microwavesynthesizer-300. The solvent was removed under reduced pressure toobtain crude product that was purified by preparative RP-HPLC (40-100%acetonitrile in water [0.1% formic acid]) to yield 35 mg (5% yield) ofthe title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.25 (s, 1H), 8.06(d, J=2.0 Hz, 1H), 7.76 (dd, J=7.6, 1.2 Hz, 1H), 7.45-7.33 (m, 5H), 7.27(dd, J=8.4, 2.4 Hz, 1H), 7.13 (t, J=7.2 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H),7.00-6.90 (m, 3H), 2.22 (s, 3H). MS (ES−) m/z 426 [M−H]−

Example 74 Methyl2-phenoxy-5-(2,4,6-trioxo-3-phenyl-1,3,5-triazinan-1-yl)benzoate

In a microwave tube previously equipped with a magnetic stirrer andnitrogen balloon was taken methyl2-phenoxy-5-[(phenylcarbamoyl)amino]benzoate (1.75 g, 4.8 mmol)(described in WO 2003029199) in bromobenzene (8.75 ml) and the mixturewas cooled to 0° C. Ethoxy carbonyl isocyanate (2.2 g, 19.3 mmol) wasadded and reaction mixture was allowed to reach room temperature andheated at 150° C. for 3 h in a microwave synthesizer. The solvent wasevaporated under reduced pressure the crude product was purified bycolumn chromatography using silica gel (100-200 mesh) and 50% ethylacetate in hexanes as an eluent to obtain 0.260 g (12% yield) of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (s, 1H), 7.92 (d,J=2.4 Hz, 1H), 7.60 (dd, J=8.8, 2.4 Hz, 1H), 7.50-7.36 (m, 7H), 7.19 (t,J=7.2 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 7.03 (d, J=7.6 Hz, 2H), 3.76 (s,3H); MS (ES−) m/z 430 [M−H]−.

Example 751-[3-(hydroxymethyl)-4-phenoxyphenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

In a RBF previously equipped with a magnetic stirrer and nitrogenballoon was taken methyl2-phenoxy-5-(2,4,6-trioxo-3-phenyl-1,3,5-triazinan-1-yl)benzoate(Example 74, 0.20 g, 0.4 mmol) in THF (2.0 ml) and the solution wascooled to 0° C. A 60% Red-Al solution in Toluene (0.186 ml, 0.5 mmol)was added drop wise and the reaction mixture was stirred for 3 h at 25°C. The reaction mixture was quenched with water (15 ml) and ethylacetate (20 ml) was added and the mixture was stirred for 10 min. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (20 ml). The combined organic layer was washed with brine(20 ml), dried over sodium sulphate and the solvent removed underreduced pressure. The crude product was purified by preparative HPLC(using 25-100% acetonitrile in water [0.1% formic acid] as mobile phase)to yield 0.006 g (13% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d₆): δ 12.00 (s, 1H), 7.58 (d, J=2.5 Hz, 1H), 7.51-7.39 (m, 7H),7.25 (dd, J=8.4, 2.0 Hz, 1H), 7.17 (t, J=7.2 Hz, 1H), 7.01 (d, J=7.6 Hz,2H), 6.89 (d, J=8.4 Hz, 1H), 5.37 (t, J=5.2 Hz, 1H), 4.58 (d, J=5.2 Hz,2H). MS (ES−) m/z 402 [M−H]−.

Example 761-{3-[2-(Dimethylamino)-2-oxoethyl]-4-phenoxyphenyl}-3-phenyl-1,3,5-triazinane-2,4,6-trione

1-(Dimethylamino)-2-[2-phenoxy-5-(3-phenylureido)phenyl]-1-ethanone(Intermediate 103, 0.05 g, 0.1 mmol) in Bromobenzene (0.5 ml) was addedto a microwave vial previously equipped with a magnetic stirrer andnitrogen balloon and the mixture was cooled to 0° C. Ethoxy carbonylisocyanate (0.05 g, 0.5 mmol) was added and the reaction mixture wasallowed to reach room temperature and heated at 150° C. for 3 h in amicrowave synthesizer. The solvent was removed under reduced pressure togive a crude product. The above steps were performed with equivalentways in 4 parallel reaction vials, which were combined duringpurification. The crude product was purified by preparative RP-HPLC(using 10-100% acetonitrile in water [0.1% formic acid] as mobile phase)to yield 0.006 g (2.5% yield) of the title compound. 1H NMR (400 MHz,DMSO-d6): δ 12.02 (s, 1H), 7.49-7.36 (m, 7H), 7.28-7.13 (m, 3H), 7.04(d, J=7.6 Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 3.72 (s, 2H), 2.99 (s, 3H),2.80 (s, 3H); MS (ES−) m/z 457 [M−H]−.

Example 771-{3-[2-(Dimethylamino)-2-oxoethoxy]-4-phenoxyphenyl}-3-phenyl-1,3,5-triazinane-2,4,6-trione

1-(Dimethylamino)-2-[2-phenoxy-5-(3-phenylureido)phenoxy]-1-ethanone(Intermediate 107, 0.50 g, 1.2 mmol) in Bromobenzene (5 ml) was added toa microwave tube previously equipped with a magnetic stirrer andnitrogen balloon, and the mixture was cooled to 0° C. Ethoxy carbonylisocyanate (0.56 g, 4.9 mmol) was added and reaction mixture was allowedto reach room temperature and heated at 150° C. for 3 h in a microwavesynthesizer. The solvent was removed under reduced pressure and thecrude product was purified by preparative RP-HPLC (using 20-100%acetonitrile in water [0.1% formic acid] as mobile phase) to yield 0.022g (3.7% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆): δ 12.07(s, 1H), 7.52-7.34 (m, 7H), 7.18-7.07 (m, 3H), 7.02-6.96 (m, 3H), 4.79(s, 2H), 2.89 (s, 3H), 2.81 (s, 3H); MS (ES−) m/z 473 [M−H]−.

The compounds below has been prepared according to analogous methods tothose described above.

Example 781-(5-Methyl-6-phenoxypyridin-3-yl)-3-(p-tolyl)-1,3,5-triazinane-2,4,6-trione

In a microwave tube previously equipped with a magnetic stirrer andnitrogen balloon was taken3-(5-Methyl-6-phenoxy-3-pyridyl)-1-(4-methylphenyl)urea (Intermediate109, 0.3 g, 0.00089 mol) in Bromobenzene (3.0 ml). The solution wascooled to 0° C. and Ethoxy carbonyl isocyanate (0.44 g, 0.00359 mol) wasadded and resulting reaction mixture was allowed to reach roomtemperature and heated at 150° C. for 3 h in an Anton paar microwavesynthesizer-300. The solvent was evaporated under reduced pressure toobtain crude product that was purified by preparative RP-HPLC (using25-100% acetonitrile in water [0.1% formic acid] as mobile phase) toyield 0.012 g (3.3% yield) of the title compound. ¹H NMR (400 MHz,DMSO-d₆): δ 12.09 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.75 (s, 1H),7.49-7.41 (m, 2H), 7.29-7.23 (m, 5H), 7.20-7.13 (m, 2H), 2.35 (s, 6H).MS (ES−) m/z 401 [M−H]−.

Biological Examples

In Vitro Assay

A high throughput cell-based screen has been used to identify positivemodulators of TrkA, TrkB and TrkC. The screen involves the use ofcell-based assay overexpressing TrkA, TrkB or TrkC. The purpose of theassay is to identify compounds that modulate neurotrophin signalling(Forsell et al 2012). The assay can be used in inhibitor mode using ahigh concentration of ligand, in modulator mode using an intermediateconcentration and in agonist mode using a low concentration of ligand.

The assay uses Enzyme Fragment Complementation (EFC) technique, which isa proximity-based assay. Briefly, cells used in this assay over-expresstwo fusion proteins, i.e. the receptor, which can be either one of TrkA,TrkB, TrkC, IGF1R or FGFR1, fused to a small peptide ofbeta-galactosidase and an adaptor protein, i.e. SHC1 (or any otherTrk-adaptor protein) fused to the major part of beta-galactosidase.Ligand binding to the receptor induces phosphorylation of theintracellular domain and hence, recruitment of the adaptor protein tothe receptor. The proximity between the small activating peptide on thereceptor and the major part of beta-galactosidase on the adaptor proteinleads to an active beta-galactosidase enzyme. The activation of thereceptor is quantified by measuring the amount of activebeta-galactosidase by its conversion of a non-luminescent substrate intoa luminescent product.

U2OS-cells, over-expressing TrkA or TrkB or TrkC, are plated in 96- or384-well plates and incubated overnight. Alternatively, cryopreservedHEK293-cells expressing IGFR1 or cryopreserved U2OS-cells expressingFGFR1 were plated in 96- or 384-well plates. On the following day, testcompound was pre-mixed with ligand (NGF, BDNF, NT-3, IGF-1 or basicfibroblast growth factor (bFGF (FGF-2))) and the ligand-compound mixtureis then added to the cells to yield a final ligand concentration of 10ng/mL. After 3 hours of incubation at room temperature, the incubationis stopped by the addition of a beta-galactosidase substrate mixturecontaining detergents. The substrate mixture is incubated for 60 minutesat ambient temperature. The luminescence is thereafter read by the useof a plate reader.

Results

Data from these assays for representative compounds is shown in theTable below. The potency is expressed as EC50 (μM) for the individualreceptors. The data indicate that the compounds of the invention areexpected to possess useful therapeutic properties.

Results

Example TrkA TrkB TrkC FGFR1 IGF1R 1 1.3 1.4 1.4 0.89 1.8 2 1.4 2.4 36.7 4 0.83 0.95 0.58 0.84 5 0.34 0.39 0.29 0.25 6 4.4 4.4 7 3.9 2.6 81.6 2.2 9 0.23 0.27 0.17 0.27 10 1.1 2.2 2.8 11 0.32 0.45 0.34 0.22 125.9 2.4 4.7 13 0.62 0.45 14 0.49 15 0.59 0.65 1.1 16 0.39 0.37 0.51 170.78 0.75 0.48 18 0.87 0.14 19 0.82 0.88 20 6.9 8.9 3.2 21 2.1 2.3 1.222 1.3 3.6 3.0 23 1.0 0.92 0.77 24 0.5 0.61 0.22 25 0.55 0.79 1.0 26 1.11.5 2.0 27 0.36 0.37 0.33 28 1.0 0.99 0.52 29 0.56 0.5 0.34 30 1.1 7.50.89 31 46 69 32 0.8 33 0.23 0.1 34 1.6 2.0 1.2 35 0.98 0.26 0.50 360.95 0.46 1.5 37 0.39 0.04 38 4.5 4.2 2.4 39 1.4 0.68 0.88 40 0.26 0.280.14 41 0.25 0.21 0.14 42 0.19 0.28 43 0.16 0.12 44 0.33 0.26 45 0.470.36 46 0.48 0.24 47 0.48 0.27 48 0.5 0.26 49 0.19 0.79 2.0 50 0.31 0.1951 0.18 0.26 52 0.38 0.41 53 0.96 0.78 54 0.44 0.31 55 0.39 1.4 56 0.290.11 0.17 57 0.18 0.12 0.09 58 0.22 0.23 0.18 59 0.48 0.46 0.33 60 0.30.22 61 0.42 0.38 62 0.93 3.18 63 2.38 0.95 64 4.4 5.9 9.6 65 4.5 1.60.32 66 0.37 0.37 67 3.2 26 68 0.23 0.36 1.1 69 0.22 0.25 0.19 70 0.660.35 71 1.66 0.61 72 0.20 0.11 73 0.14 0.10 74 0.58 0.54 75 1.17 1.8 7633 4.53 77 0.43 0.36 78 3.51 3.83

In Vivo Assay

Passive Avoidance Task

Passive avoidance (PA) is an aversive learning task based on classical(Pavlovian) fear conditioning that allows for analysis of bothfacilitation and impairment of memory function by adjusting theunconditioned stimulus, i.e. the electrical foot shock. Commonly acognitive-impairing agent is administered to the animals to mimic theneurochemical disturbances present in various cognitive disorders e.g.cholinergic (scopolamine) and glutamatergic (MK-801) deficits.

Prior to testing, the animals are brought to the experimental room wherethey are allowed to habituate for 60 min. The test is conducted using amodified shuttle box with two communicating compartments of equal sizewith a small sliding door built into the separating wall and astainless-steel bar floor. One of the compartments is not illuminatedand thus black whereas the other compartment (the light one) isilluminated by an electric bulb, installed on the top of a plexiglasscover. The PA training is conducted in a single session. The animals areallowed to explore the compartment for 60 sec, after which the slidingdoor is automatically opened and the mouse is allowed to cross over intothe dark compartment. Once the mouse has entered the dark chamber withall four feet, the sliding door is automatically closed and a scrambledelectrical current is delivered through the grid floor. Latency to crossover into the dark compartment (training latency) is recorded. Retentionlatencies as well as total time spent in bright compartment are tested24 h later (day two). The animals are placed in the light compartmentand allowed to explore for 15 sec, where upon the sliding door is openedallowing free access to the dark compartment for a period of 300 sec.The latency to cross over into the dark compartment with all four feetis measured (retention latency) as well as time in bright compartmentand a number of other relevant parameters (e.g. number of visits in thedark compartment).

In in vivo study 1, vehicle (20% DMSO in 0.1M PBS) or different doses ofExample 5 were administered to C57/Bl6 mice once per day (s.c.administration) for 4 days prior to PA training. PA training was thenperformed according to the procedure described above. On the day of PAtraining, scopolamine at 0.3 mg/kg, or vehicle, was administeredsubcutaneously 30 min prior to training. Data on retention latency shownin FIG. 1.

Abbreviations

DCM—Dichloromethane

MeOH—methanol

TEA—triethylamine

RBF—round bottom flask

EtOAC—ethyl acetate

ACN—acetonitrile

RT—room Temperature

TFA—trifluoroacetic acid

DEAD—diethyl azodicarboxylate

RB—round bottom

THF—tetrahydrofuran

Pd/C—palladium on carbon

h—hours

min—minutes

combi chromatography—combi flash chromatography

column chromatography—flash chromatography

HATU—1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate

DMF—dimethylformamide

NMP—N-methyl-2-pyrrolidone

RP-HPLC—reverse phase high performance liquid chromatography

The invention claimed is:
 1. A compound of formula (I), wherein thecompound is1-(3-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione,

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient.